CN102985125A - Dry powder drug delivery system and methods - Google Patents

Dry powder drug delivery system and methods Download PDF

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Publication number
CN102985125A
CN102985125A CN2011800309664A CN201180030966A CN102985125A CN 102985125 A CN102985125 A CN 102985125A CN 2011800309664 A CN2011800309664 A CN 2011800309664A CN 201180030966 A CN201180030966 A CN 201180030966A CN 102985125 A CN102985125 A CN 102985125A
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inhaler
dry powder
cartridge
powder
container
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CN2011800309664A
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Chinese (zh)
Inventor
查得·C·斯穆尼
班诺特·阿达莫
约翰·M·波利多洛
P·斯般瑟儿·堪赛
丹尼斯·欧文菲尔德
卡尔·萨伊
克里斯汀·碧灵斯
马克·T·马力诺
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曼金德公司
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Priority to US35703910P priority Critical
Priority to US61/357,039 priority
Priority to US41177510P priority
Priority to US61/411,775 priority
Application filed by 曼金德公司 filed Critical 曼金德公司
Priority to PCT/US2011/041303 priority patent/WO2011163272A1/en
Publication of CN102985125A publication Critical patent/CN102985125A/en

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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00Inhalators
    • A61M15/0091Inhalators mechanically breath-triggered
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00Inhalators
    • A61M15/0001Details of inhalators; Constructional features thereof
    • A61M15/0021Mouthpieces therefor
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00Inhalators
    • A61M15/0001Details of inhalators; Constructional features thereof
    • A61M15/0021Mouthpieces therefor
    • A61M15/0025Mouthpieces therefor with caps
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00Inhalators
    • A61M15/0028Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M15/00Inhalators
    • A61M15/0028Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up
    • A61M15/003Inhalators using prepacked dosages, one for each application, e.g. capsules to be perforated or broken-up using capsules, e.g. to be perforated or broken-up
    • A61M15/0043Non-destructive separation of the package, e.g. peeling
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M11/00Sprayers or atomisers specially adapted for therapeutic purposes
    • A61M11/06Sprayers or atomisers specially adapted for therapeutic purposes of the injector type
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2202/00Special media to be introduced, removed or treated
    • A61M2202/06Solids
    • A61M2202/064Powder
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00General characteristics of the apparatus
    • A61M2205/60General characteristics of the apparatus with identification means
    • A61M2205/6045General characteristics of the apparatus with identification means having complementary physical shapes for indexing or registration purposes
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61MDEVICES FOR INTRODUCING MEDIA INTO, OR ONTO, THE BODY; DEVICES FOR TRANSDUCING BODY MEDIA OR FOR TAKING MEDIA FROM THE BODY; DEVICES FOR PRODUCING OR ENDING SLEEP OR STUPOR
    • A61M2205/00General characteristics of the apparatus
    • A61M2205/60General characteristics of the apparatus with identification means
    • A61M2205/6063Optical identification systems
    • A61M2205/6081Colour codes

Abstract

A pulmonary drug delivery system Is disclosed, including a breath-powered, dry powder inhaler, and a cartridge for delivering a dry powder formulation. The inhaler and cartridge can be provided with a drug delivery formulation comprising, for example, a diketopiperazine and an active ingredient, Including, small organic molecules, peptides and proteins, including, insulin and g!ucagon-i!ke peptide (1) for the treatment of disease and disorders, for example, endocrine disease such as diabetes and/or obesity.

Description

干粉药物输送系统和方法 Dry powder drug delivery systems and methods

[0001] 相关串请的交叉引用 [0001] Cross-Reference to Related string Please

[0002] 本申请要求2010年11月9日提交的美国临时专利申请No. 61/411,775和2010年6月21日提交的美国临时专利申请No. 61/357,039的权益,这两件申请的全部公开内容通过引用结合于此。 [0002] This application claims filed November 9, 2010 of US Provisional Patent Application No. 61 / 411,775 and US Provisional Patent June 21, 2010 filed Application No. 61 / 357,039, the two the entire disclosure of application was incorporated by reference herein.

技术领域 FIELD

[0003] 本公开涉及用于为治疗疾病或失调向肺呼吸道和肺循环输送药物的干粉吸入系统,该干粉吸入系统包括干粉吸入器、盒和药物组合物。 [0003] The present disclosure relates to a dry powder for treatment of a disease or disorder delivery of drugs to the airways of the lungs and pulmonary circulation inhalation system, the dry powder inhalation system comprises a dry powder inhaler, the cartridge and pharmaceutical compositions thereof. ·背景技术 ·Background technique

[0004] 将活性成分引入到循环系统的用于疾病治疗的药物输送系统有很多,并且包括口月艮,透皮吸收,吸入,皮下和静脉注射。 [0004] The active ingredient is incorporated into the drug delivery system for the treatment of circulatory system diseases are numerous and include oral months Burgundy, transdermal absorption, inhalation, subcutaneous and intravenous. 通过吸入来输送的药物通常利用在空气中相对于大气压力的正压来输送。 Drug delivery by inhalation typically utilize a positive pressure relative to atmospheric air pressure be conveyed. 近年来,已经利用干粉吸入器实现了向肺组织的药物输送。 In recent years, the use of dry powder inhalers achieve the delivery of drug to the lung tissue. 干粉吸入器可以是呼吸驱动或呼吸供能的,并且通过将载体中的药物颗粒转化为细小的干粉来输送药物,其中该细小的干粉被夹带到空气中并且被病人吸入。 The dry powder inhaler may be a breath actuated or energized breathing, and the drug carrier particles by converting to a fine dry powder medication delivery, wherein the fine powder is entrained into the air and is drawn into the patient. 利用干粉吸入器输送的药物不再仅用于治疗肺疾病,而且还能被吸收到体循环中,使它们可用于治疗很多疾病,包括但不限于糖尿病和肥胖症。 Using a dry powder inhaler delivered drug is no longer only used for the treatment of lung diseases, but also is absorbed into the systemic circulation, making them useful for treating many diseases, including but not limited to, diabetes and obesity.

[0005] 用于向肺输送药物的干粉吸入器包括粉末制剂的加药系统,该粉末制剂通常散装供应或者量化为存储在单位剂量室(例如硬胶囊或泡罩包装)中的个人剂量。 [0005] for delivering a drug to the lungs of dry powder inhaler formulation comprising a powder dosing system, the powder formulation is typically stored in bulk supply or quantified as individual dose (e.g. hard gelatin capsules or blister packs) in the unit dose chamber. 散装容器装配有由患者操作的测量系统,以在吸入之前从粉末中分离出来单次剂量。 Bulk vessel equipped with a measuring system operated by the patient to separate from the powder out of a single dose prior to inhalation. 加药的重复性要求药物制剂是均匀的并且要求剂量可以连贯并且可重复地输送给患者。 Dosing reproducibility requires drug formulation is uniform and consistent doses may be required and may be repeatedly delivered to the patient. 因此,加药系统在当患者用药时的吸气动作期间,理想地操作以有效地完全排出全部药物。 Thus, when the suction system dosing operation when a patient during treatment, it is desirable to effectively operate all the drug is completely discharged. 然而,只要能够实现可重复给药,则通常不需要完全排出。 However, repeated dosing may be as long as possible, usually need not be completely discharged. 对于散装容器,粉末制剂的流动性和长期的物理和机械稳定性这方面,对于散装容器来说比对于单个单位剂量容器更为关键。 For bulk containers, the flowability of the powder formulation and long-term physical and mechanical stability in this area, is more critical for bulk containers than for a single unit dose containers. 对于诸如泡罩之类的单位剂量室来说更容易实现良好的防潮保护。 For unit dose blister such as a room, it is easier to achieve good moisture protection. 然而,用于制造泡罩的材料允许空气进入药物室并且其后药物随着长期储存而失效。 However, the material used to manufacture the blister allow air into the drug chamber and thereafter long-term storage as a pharmaceutical fail. 此外,由于泡罩的穿刺膜(puncturingfilm)或剥离膜所产生的空气导管结构的变化,通过吸入、利用泡罩以输送药物的干粉吸入器遭受向肺部给药的不连贯。 Further, due to changes in the air conduit structure blister piercing the membrane (puncturingfilm) or film produced by inhalation, a blister to deliver medicament using a dry powder inhaler for pulmonary administration to a subject to incoherence.

[0006] 本领域中的干粉吸入器通过在药盒或小盒内对粉末制剂进行解聚、可以在吸气动作期间产生药物颗粒或适合的吸入羽流(inhalation plume)。 [0006] Those skilled in the dry powder inhaler cartridge or a small box by the powder formulation depolymerization may be generated drug particles or suitable inhalation plumes (inhalation plume) during the suction operation. 在吸入期间从吸入器的嘴部(mouthpiece)排出的细小干粉的量,很大程度上取决于例如粉末制剂中的颗粒间附着力和吸入器将那些颗粒分离开以使它们适合吸入的效率。 Amount discharged from the nozzle portion of the inhaler (mouthpiece) during inhalation of fine dry powder, for example, depends largely on powder formulation between the particles and the adhesion of the inhaler those particles separated so that they are suitable for inhalation efficiency. 经由肺循环输送药物的好处很多,并且可以包括快速进入动脉循环,避免肝脏代谢药物降解,易于使用,即没有通过其他分配路径进行分配的不舒适。 Many benefits of drug delivery via the pulmonary circulation, and can include quick access to the arterial circulation, to avoid degradation of the liver metabolism of drugs, easy to use, that is not distributed through other distribution paths uncomfortable.

[0007] 由于缺乏实用性和/或制造成本,用于肺部给药的已开发的干粉吸入器迄今为止已取得了有限的功效。 [0007] due to lack of practicality and / or manufacturing costs, has developed a dry powder inhaler for pulmonary administration has so far been met with limited efficacy. 现有技术的吸入器存在的一些长期问题包括缺乏设备的耐用性、剂量不连贯、设备不便,解聚性差,根据从推进剂使用分离的输送的问题,和/或缺乏患者的依从性。 Some long-term problems in the prior art inhaler devices include the lack of durability, the dose incoherent apparatus inconvenience depolymerization poor The problem with using separate from the propellant delivery, and / or lack of patient compliance. 因此,发明人已确定了设计和制造具有连贯性的粉末输送性能、容易使用无不适以及允许更好的患者依从性的离散(discrete)吸入器配置的吸入器的需求。 Accordingly, the inventors have determined the design and manufacture of powder delivery performance of a coherent, easy to use without discomfort, and allow for better patient compliance requirements discrete (Discrete) disposed inhaler inhaler.

发明内容 SUMMARY

[0008] 本文所描述的一般地是用于肺部给药的干粉吸入器系统,其中所述系统包括干粉吸入器和包括用于干粉吸入器的药盒的容器,以将干粉制剂迅速有效地输送到肺呼吸道。 [0008] Generally described herein are dry powder inhaler systems for pulmonary administration, wherein the system comprises a dry powder inhaler comprising a cartridge and a dry powder inhaler container, in order quickly and effectively to a dry powder formulation delivered to the airways of the lungs. 吸入系统的干粉制剂包括用于治疗一种或多种疾病的活性剂,所述一种或多种疾病包括局部或全身疾病或功能紊乱,包括但不限于糖尿病、肥胖症、疼痛、诸如偏头痛等头痛、中枢或周围神经系统和免疫系统疾病等,以及用于疫苗配方的输送。 Inhalation system comprises a dry powder formulation for treating one or more diseases of the active agent, the one or more diseases including topical or systemic diseases or disorders, including but not limited to, diabetes, obesity, pain, such as migraine such as headache, central or peripheral nervous system and immune system diseases, as well as transport for vaccine formulations. 干粉吸入器可以是呼吸供能的、紧凑的、可重复使用或一次性的系统,其可以具有各种形状和尺寸,并且包括用于有效和迅速的输送干粉药物的空气流管道通路。 The dry powder inhaler may be a breath powered, compact, reusable or disposable system, which may have various shapes and sizes, and comprising an air flow conduit effective and rapid passage of the dry powder drug delivery. 在一个实施例中,吸入器可以是有药盒或无药盒情况下使用的单位剂量的、可重复使用或一次性的吸入器。 In one embodiment, the inhaler is a unit dose may be used in a kit or kit no circumstances, reusable or disposable inhaler. 在无药盒的情况下使用,我们指的是这样的系统,其中设置了类似于药盒的结构并且该结构集成到吸入器,并且该吸入器是单次使用和一次性的。 Used without cartridge cases, we refer to such a system, in which a structure similar to the kit and the structure is integrated into the inhaler, and the inhaler is a single-use and disposable. 或者,在某些实施例中,系统包括单独地设置并且安装到例如由用户使用的吸入器中的药盒。 Alternatively, in some embodiments, the system includes a separately provided and mounted to the inhaler cartridge used by the user, for example. 在该实施例中,吸入器是可重复使用的吸入器,并且每次使用时在吸入器中安装新药盒。 In this embodiment, the inhaler is reusable inhaler, and install a new cartridge each time when used in an inhaler. 在另一实施例中,吸入器是一次性或可重复使用的多次剂量吸入器,其可以使用单次单位剂量药盒,其安装在吸入器中,或者安装在内置于吸入器或结构上作为吸入器的一部分配置的类药盒结构中。 In another embodiment, the inhaler is a disposable or reusable multiple dose inhalers which use a single unit dose cartridge mounted on the inhaler, placed on or attached to the inner structure of an inhaler or as part of a configuration of an inhaler cartridge class structure.

[0009] 在又一实施例中,干粉吸入系统包括有药盒或无药盒的干粉吸入设备或吸入器,以及包括用于肺部给药的活性成分的药物制剂。 [0009] In yet another embodiment, the dry powder inhalation system comprises a kit or kit-free dry powder inhaler device or inhaler, and a pharmaceutical formulation comprising an active ingredient for pulmonary administration. 在某些实施例中,粉末输送是到达包括肺泡区域的深肺的,并且在这些实施例的某些实施例中,活性剂被吸收到肺循环中用于全身输送。 In certain embodiments, comprises a powder delivery is reaching the deep lung alveolar region, and, in certain embodiments these embodiments, the active agent is absorbed into the pulmonary circulation for systemic delivery. 系统还可包括有或无单位剂量药盒的干粉吸入器以及药物输送制剂,该药物输送制剂包括例如二酮哌嗪以及诸如小分子、包括胰岛素和胰高血糖素样肽I的肽、多肽和蛋白质等的活性成分。 The system may also include a cartridge with or without a unit dose dry powder inhaler formulation and drug delivery, the drug delivery formulation comprising a diketopiperazine and such as, for example, small molecules, including insulin and glucagon-like peptide I, peptide, polypeptide, and proteins and other active ingredients.

[0010] 在一个实施例中,干粉吸入器包括壳体、可移动组件和嘴部,其中可移动组件可操作地配置成将容器从粉末保持位置移动到给药位置。 [0010] In one embodiment, a dry powder inhaler comprises a housing, a movable assembly and the mouth portion, wherein the movable assembly is operatively configured to move from a powder container holding position to the administering position. 在该实施例和其他实施例中,可移动组件可以是通过各种机构可移动的滑板、滑动托盘或溜板。 In this embodiment and other embodiments, the movable component by a variety of means may be a movable slide, carriage or slide tray.

[0011] 在另一实施例中,干粉吸入器包括结构上配置成具有打开位置的壳体和嘴部,以及可操作地配置成接收、保持药盒和根据吸入器从打开位置到关闭位置的移动把药盒从保持位置重新配置到配药、给药或药物输送位置的结构。 [0011] In another embodiment, a dry powder inhaler comprises a housing configured to have a structure and an open position of the mouth, and operably configured to receive, and a cartridge holder according to the inhaler from the open position to the closed position moving the cartridge from the holding position to reconfigure dispensing structure, administration or drug delivery position. 在本实施例的版本中,当吸入器打开以卸载已使用的药盒时,该机构还可以在使用后将安装在吸入器中的药盒从给药位置重新配置到更换位置,从而提示用户药盒已经用尽。 Kit version of this embodiment, when the inhaler is opened to unload the cartridge has been used, the mechanism may also be used after mounted in the inhaler from the dosing position to reconfigure to the replacement position, thereby prompting the user The kit has been exhausted. 在一个实施例中,该机构可在使用后将药盒重新配置到可处理或丢弃位置。 In one embodiment, the mechanism may be used to reconfigure the cartridge after processing or may discard position. 在这样的实施例中,壳体在结构上被配置成通过包括铰链等的各种机构可移动地连接到嘴部。 In such an embodiment, the housing being structurally configured to nozzle portion includes a hinge mechanism such as the various movably connected to. 被配置成接收安装在吸入器中的药盒并将其从保持位置重新配置到给药位置的机构,可被设计为基于吸入器组件的运动(例如从打开配置关闭设备)手动或自动地操作。 Is configured to receive a mounting cartridge in the inhaler and reconfigure from the holding position to the administering position of the mechanism, the movement can be designed based on the suction assembly (e.g. closing device from the open configuration) manually or automatically operated . 在一个实施例中,用于重新配置药盒的机构包括连接到嘴部并可移动地连接到壳体的滑动托盘或滑板。 In one embodiment, the means for reconfiguring the kit comprises a slide plate connected to the slide tray or the mouth portion and movably coupled to the housing. 在另一个实施例中,该机构被安装到或适用于吸入器并且包括集成地安装在例如吸入器设备的铰链内的齿轮机构。 In another embodiment, the mechanism is mounted or adapted to the inhaler and comprises a gear mechanism integrally mounted within, for example, a hinge of the inhaler device. 在又一实施例中,被可操作地配置成接收药盒并将药盒从保持位置重新配置到给药配置的机构,包括凸轮,该凸轮能够基于例如壳体或嘴部的旋转重新配置药盒。 In yet another embodiment, the cartridge operably configured to receive and reconfigure the cartridge from a position holding mechanism configured to administration, comprising a cam capable of reconfiguration based on the rotation drug portion such as a housing or mouth box.

[0012] 在替换实施例中,干粉吸入器可以制作为单次使用、单位剂量的一次性吸入器,其可设置有配置成保持粉末药物的容器,并且该容器可由用户从保持配置移动到给药配置,其中吸入器可具有第一和第二配置,其中第一配置是保持配置并且第二配置是定量给药的给药配置。 [0012] In alternative embodiments, the dry powder inhaler can be made as a single use, unit dose disposable inhaler, which may be provided with a container configured to hold a powder medicament, and the container may be moved from the holding to the user to configure drug configuration in which inhaler can have a first and a second configuration, wherein the first configuration and the second configuration is configured to maintain the configuration of dosing was administered. 在该实施例中,吸入器可设置成具有或无用于重新配置粉末容器的机构。 In this embodiment, the inhaler may be provided with or without means for reconfiguring the powder container. 根据后面的实施例的粉末,容器可以直接由用户重新配置。 The powder embodiment of the latter embodiment, the container can be reconfigured directly by the user. 在该实施例的某些方面,吸入器和容器可被制造为两件式吸入系统,其中粉末药物在将设置组装为保持位置之前,被提供到容器中。 In some aspects of this embodiment, the inhaler and container may be manufactured as a two-piece intake system, in which the powder medicament in the holding position arranged prior to assembly, is provided to the vessel. 在该实施例中,容器被连接到吸入器体,并且容器可例如通过相对于包括嘴部的吸入器的顶部滑动、从保持配置移动到给药配置。 In this embodiment, the container is connected to the inhaler body and inhaler container may for example comprise a top nozzle portion slidably disposed from the holding by the configuration of the mobile with respect to the administration.

[0013] 在又一实施例中,吸入器包括配置成接收容器的容器安装区域,以及具有至少两个进气孔和至少一个出气孔的嘴部;其中所述至少两个进气孔的一个进气孔与容器区域流体地连通,并且所述至少两个进气孔中的一个经由被配置成绕过容器区域的流动通路与所述至少一个出气孔流体地连通。 [0013] In yet another embodiment, the inhaler comprising a container mounting area configured to be received in the container, and the nozzle portion having at least two inlet and at least one vent hole; and wherein two of the at least one inlet opening intake port fluidly communicates with the container area, and wherein the at least two inlet hole in a bypassing flow passage area of ​​the container is arranged via at least one vent in fluid communication.

[0014] 在一个实施例中,吸入器具有诸如接触用户的唇部或嘴的近端和远端等的相对两端,并且包括嘴部和药物容器;其中所述嘴部包括上表面和底部或下表面。 [0014] In one embodiment, the inhaler has opposing ends such as a contact or a user's mouth lip proximal and distal ends and the like, and comprising a medicament container and a mouth portion; wherein said nozzle portion includes an upper surface and a bottom or the lower surface. 嘴部下表面具有第一区域和第二区域,第一区域被配置成相对平坦以将容器维持在密封或保持配置,并且第二区域邻近第一区域并相对于第一区域凸起。 A first nozzle having a lower surface region and a second region, the first region is configured to be relatively flat or maintained in the sealed container holding configuration, and a second region adjacent the first region and the first region with respect to the projection. 在该实施例中,容器可从保持配置移动到给药配置并且反之亦然,并且在给药配置中,嘴部下表面的第二凸起区域和容器形成或限定了空气进入通路,该空气进入通路允许环境空气进入容器的内部体积或将容器的内部体积暴露给环境空气。 In this embodiment, the container may be configured to move from holding dosing configuration and vice versa, and in the dosing configuration, the lower surface of the second nozzle and the container are formed or raised area defining a passageway into the air, the air enters passage allowing ambient air into the interior volume of the container or the interior volume of the container is exposed to ambient air. 在一个实施例中,嘴部可具有多个开口,例如进气口、出气口以及用于在配药或给药位置与药物容器连通的至少一个开口,并且嘴部可被配置成具有一体连接的板,该板从吸入器的底表面侧边延伸并且具有向吸入器嘴部突出的凸缘,该凸缘用作嘴部上的容器的轨道和支撑,以使得容器能够沿着轨道从保持位置移动到配药或给药位置并且如果需要则退回到保持位置。 In one embodiment, the nozzle portion may have a plurality of openings, such as inlet, outlet and means for dispensing or dosing position of at least one opening in communication with the drug container, and the mouth portion may be configured to have integrally connected a plate extending from the bottom surface sides of the inhaler and the inhaler to the mouth portion having a projecting flange which serves as a support rail and on the container mouth portion, so that the container can be maintained from a position along the rail to move dispensing or dosing position and if necessary, return to the holding position. 在一个实施例中,药物容器配置有从其上边缘延伸以适用于嘴部板上的凸缘的翼状突起或小翼。 In one embodiment, the medicament container is disposed to extend from the upper edge of the wing-like portion applicable to the mouth plate flange projections or winglets. 在一个实施例中,药物容器可以滑板、滑动托盘或溜板的方式、由用户从保持位置移动到给药位置并且在给药后退回到保持位置。 In one embodiment, the medicament container may slide, slidably tray or slide plate is moved by the user from the holding position to the administering position and retracted back to the holding position in the administration.

[0015] 在另一个实施例中,单次使用、单位剂量、一次性的吸入器可被构造为具有滑板,滑板结合并可操作地配置到嘴部。 [0015] In another embodiment, a single use, unit dose, disposable inhaler can be configured with a slider, the slider and operatively arranged in conjunction to the mouth portion. 在该实施例中,在滑板上的桥部可以紧靠或依靠在药物容器的区域上、以沿着嘴部板轨道将容器从保持位置移动到配药或给药位置。 In this embodiment, the bridge portion on the slide may abut or rest on regional drug container to move the container from the holding position along the rail to the plate portion of the nozzle dispensing or dosing position. 在该实施例中,滑板可手动地操作以移动在嘴部轨道上的容器。 In this embodiment, the slide may be manually operated to move the container on the mouthpiece of the track.

[0016] 在一个实施例中,干粉吸入器包括一个或多个空气入口和一个或多个空气出口。 [0016] In one embodiment, a dry powder inhaler comprises one or more air inlets and one or more air outlets. 当吸入器关闭时,至少一个空气入口可以允许气流进入吸入器,并且至少一个空气入口允许气流进入药盒室或药盒的内部或适用于吸入的容器。 When the inhaler is closed, at least one air inlet may allow airflow into the inhaler, and the at least one air inlet to allow air flow into the interior chamber cartridge or kit or container suitable for inhalation. 在一个实施例中,吸入器具有开口,该开口在结构上被配置成当药盒容器处于给药位置时、与药盒放置区域并且与药盒进气口连通。 In one embodiment, the inhaler has an opening, the opening is configured to, when the cartridge container is in the administering position, communicates with the cartridge placement area and with a cartridge in the intake port structure. 进入药盒内部的气流可通过排出口或给药口(一个或多个)从药盒排出;或者进入吸入器的容器的气流可通过给药口的至少一个排出。 Air flow into the interior of the cartridge from the cartridge may be discharged through the discharge port or ports administration (s); or the inhaler into the air container may be discharged through at least one administration port. 在该实施例中,药盒进气口( 一个或多个)在结构上被配置成使得,进入药盒内部的空气流的全部或一部分被引导至排出口或给药口(一个或多个)。 In this embodiment, the cartridge inlet port (s) is configured such that in the structure, the interior of the cartridge into the whole or part of the air flow is directed to the outlet opening or dosing (one or more ). [0017] 药物容器在结构上被配置成具有能够引导空气流的两个相对的、相对曲线形状的侧面。 [0017] The medicament container is configured with two opposing air flow can be guided in the opposite side of the curve shape in the structure. 在该实施例中,在吸入期间进入空气入口的气流可以绕与给药口的轴线相对垂直地轴、在容器的内部循环,并且从而气流可以升起、翻腾并有效地流化装在药盒中的粉末药物。 In this embodiment, the air flow during inhalation air enters the inlet about an axis perpendicular to the axis opposite the mouth of the administration, internal circulation in the container, and thus the air flow can be raised, and effectively churn flow of make-up in the kit powdered medicament. 在该实施例和其他实施例中,在空气管道中的流化粉末通过在流动通路中的方向或速度(即颗粒的加速度或减速度的变化)、可进一步被解聚成更细小的粉末颗粒。 In this embodiment and other embodiments, fluidized powder in the air duct by the direction or speed (i.e., the change in acceleration or deceleration of the particles) in the flow passage, can be further depolymerized into finer powder particles. 在某些实施例中,加速度或减速度的变化可通过改变例如给药口( 一个或多个)、嘴部管道和/或其界面的角度和几何形状来实现,在这里所述的吸入器中,随着颗粒穿过吸入器的颗粒的流化和加速机制是实现干粉制剂的解决和输送的方法。 In certain embodiments, the change in acceleration or deceleration can be altered, for example, by oral administration (s), the mouth of the conduit and / or the angle and geometry of the interface is achieved, the inhaler herein , as the particles pass through the particle fluidizing and acceleration mechanism is to solve the inhaler and method for delivering a dry powder formulation of implementation.

[0018] 在特定实施例中,用于解聚和分散粉末制剂的方法包括一个或多个步骤,诸如通过进入容器的气流启动并加强的主要容器区域的翻腾;在通过离开容器的给药口的气流中的粉末的较快加速;在粉末排出给药口时通过方向或速度的改变引起的粉末进一步加速;在流动梯度内导致的粉末颗粒的剪切,其中颗粒的上部的流动比颗粒下部的流动块;由于在嘴部空气管道内的横截面积的增大而导致的流动的减速;由于颗粒从较高压力区移动到较低压力区而导致的困在颗粒内的空气的膨胀,在流动通路中的任意点处的颗粒与流动管道之间的碰撞。 Method [0018] In certain embodiments, for depolymerization and dispersible powders formulations include one or more steps, such as start somersault region and strengthen the main air flow through the container into the container; a dosing opening through leaving the vessel the gas stream accelerating faster powder; the direction or velocity when administered powder discharge port to further accelerate the powder caused by the change; shear gradients result in the flow of powder particles, wherein the particles of the upper portion of the flow of the lower portion than the particle flow block; flow reduction due to the increased cross-sectional area of ​​the air duct in the mouth portion of the resulting; expanded air trapped in the particles due to particle moving from a higher pressure region to a lower pressure zone caused, collisions between particles and flow conduit at any point in the flow passage.

[0019] 在另一个实施例中,干粉吸入器包括嘴部;滑板、滑动托盘或溜板;配置成实现滑板或滑动托盘的运动的壳体,铰链和齿轮机构;其中嘴部和壳体通过铰链可移动地连接。 [0019] In another embodiment, the dry powder inhaler includes a nozzle portion; slide, carriage or slide tray; configured to implement housing, the hinge and gear mechanism or a sliding motion of slide tray; and wherein the mouth through the housing the hinge movably connected.

[0020] 与干粉吸入器一起使用的药盒可被制造成装有用于吸入的任意干粉药物。 [0020] A kit for use with a dry powder inhaler may be manufactured with any dry powder medicament for inhalation. 在一个实施例中,药盒在结构上被配置成适用于特定的干粉吸入器,并且可以根据一起使用的吸入器的形状和尺寸(例如,如果吸入器具有允许平移运动或旋转运动的机构)、以任意尺寸和形状来制造。 In one embodiment, the cartridge is structurally configured to be suitable for a particular dry powder inhaler, and may be the shape and size of an inhaler for use with (e.g., if the inhaler has a mechanism to allow rotational movement or translational movement) , any size and shape to be manufactured. 在一个实施例中,药盒可配置有紧固机构,例如,在药盒顶部具有与吸入器中的相配合的斜边对应的斜边,以使得使用时药盒被紧固。 In one embodiment, the kit may be configured with fastening means, e.g., an inhaler having cooperating oblique at the top corresponding to the hypotenuse kit to use the kit is such that when fastened. 在一个实施例中,药盒包括容器和盖或盖子,其中容器可适用于盖部的表面,并且容器可相对于盖部移动,或者盖部在容器上可移动并且可根据它的位置得到各种配置,例如保持配置、给药配置或使用后配置。 In one embodiment, the kit comprises a container and a lid or cover, wherein the container portion applicable to the surface of the cover and the container may be moved relative to the cover portion, or the cover portion is movable on the container and can be obtained in accordance with its respective position configurations, such as maintaining the configuration, the configuration after administration or configuration.

[0021] 示例性实施例可包括保持药物的封装,该封装配置成具有至少一个进气孔以允许气流进入封装;至少一个给药孔以允许气流从封装排出;所述进气孔配置成响应于压力梯度、引导在给药孔处或在封装内靠近给药孔的颗粒处的气流的至少一部分。 [0021] The exemplary embodiments may include maintaining a drug package, the package is configured with at least one inlet opening to allow airflow into the package; administered at least one aperture to permit airflow discharged from the package; said air inlet port configured to respond the pressure gradient, at least a portion of the airflow guide hole administered at or near the delivery opening in the package at the particles. 给药孔(一个或多个)和进气孔各个单独地具有诸如长方形、矩形、圆形、三角形、方形和椭圆形的形状,并且可以相互靠近。 The delivery opening (s) and has an individual inlet holes such as oblong, rectangular, circular, triangular, square and elliptical shape, and may be close to each other. 在吸入期间,在吸入位置中,适用于吸入器的药盒允许空气流进入封装并与粉末混合以流化药物。 During inhalation, the inhalation position for allowing the inhaler cartridge air flow into the package and mixed with the powder to fluidize the medicament. 流化的药物在封装内运动使得药物逐渐通过给药孔排出封装,其中正排出给药孔的流化药物被并非源于封装内部的第二气流剪切并冲淡。 Fluidized drug encapsulated within the package movement so that the drug is gradually discharged through the delivery opening, wherein the discharge flow of the drug administration the positive hole is not derived from a second airflow inside the package cutting and diluted. 在一个实施例中,在内部体积中的空气流以环形方式旋转以升起在容器或封装中的粉末药物,并且使被夹带的粉末颗粒或粉末团在容器的内部体积中再循环、以在颗粒排出容器或一个或多个吸入器进气口或空气入口或给药孔之前促进气流翻腾,并且其中再循环的气流能够引起翻腾,或者在内部体积中的空气的非漩涡流用来解聚药物。 In one embodiment, the air stream in the interior volume to raise an annular rotating manner in a container or package powdered medicament, and the powder particles or powder mass entrained in the recirculation of the interior volume of the container, in order to particles of one or more discharge container or inhaler air inlet or air inlet aperture or administered before churning promote airflow, and wherein the recycle gas stream can cause tumbling, or a non-swirling flow of air in the internal volume for DEPOLYMERIC . 在一个实施例中,旋转的轴线几乎与重力方向垂直。 In one embodiment, the axis of rotation almost perpendicular to the direction of gravity. 在另一实施例中,旋转的轴线几乎与重力方向平行。 In another embodiment, the axis of rotation is almost parallel to the direction of gravity. 并非源于封装内部的第二气流进一步用来解聚药物。 The second gas stream does not originate from inside the package for further depolymerization drugs. 在该实施例中,通过用户的吸气产生压差。 In this embodiment, the intake pressure difference is generated by the user. 用于干粉吸入器的药盒包括:配置成保持药物的封装;允许气流进入封装的至少一个进气口;以及允许气流排出封装的至少一个给药口;所述至少一个进气口配置成响应于压差、在封装内的所述至少一个给药口处引导进入所述至少一个进气口的气流的至少一部分。 A kit for a dry powder inhaler comprising: a package configured to hold a medicament; allows airflow into the enclosing at least one air inlet; and allowing the gas stream exiting the at least one dosing opening of the package; the at least one intake port configured to respond differential pressure, said at least one package in the administration of at least a portion of the guide opening into the at least one air inlet airflow.

[0022] 用于吸入器的单位剂量容器包括:基本平整的药盒顶部,箭头状配置,其具有一个或多个进气孔、一个或多个给药孔以及向下延伸的两个侧板,两个侧板每一个均具有轨道;以及容器,该容器可移动地配合到药盒顶部的侧板,并且该容器包括配置成具有相对杯状结构的室和限定内部体积的内表面,其中所述杯状结构具有两个相对平坦且平行的侧面和相对圆形的底部;该容器可配置成与药盒顶部一起实现保持位置和给药位置;其中在与干粉吸入器一起使用时,在吸入期间,进入内部体积的气流随着其进入内部体积而分开,气流的一部分通过一个或多个给药孔排出,并且气流的一部分在通过给药孔排出之前在内部体积的内部旋转并升起内部体积中的粉末。 [0022] Unit dose container for an inhaler comprising: a substantially flat cartridge top, arrow-shaped configuration, having one or more inlet holes, administration of the one or more holes and two downwardly extending side plates , two side panels each having a rail; and a container movably fitted to the top of the cartridge side, and the container includes a chamber configured to have an inner surface defining an internal volume and relative cup structure, wherein the cup-shaped structure having two relatively flat and parallel sides and rounded bottom opposite; container may be configured to implement the holding position and the administering position with the cartridge top; wherein when used with a dry powder inhaler, at the during inhalation, air entering the interior volume as it enters the internal volume of the separated part of the gas stream is discharged through one or more apertures administration, and a portion is discharged through the delivery opening before the interior of the whirling airflow inside the volume rises and the internal volume of the powder.

[0023] 在一个实施例中,提供了用于肺部药物输送的吸入系统,其包括:干粉吸入器,该干粉吸入器包括壳体和嘴部,嘴部具有进气口和出气口、在进气口和出气口之间的空气管道以及结构上配置成接收药盒的开口;诸如滑板等的药盒安装机构;药盒,其配置成适用于干粉吸入器并且装有用于吸入的干粉药物;其中药盒包括容器和具有一个或多个进气口或者一个或多个给药口的盖部;使用中的干粉吸入器系统具有相对于被输送给患者的总气流通过药盒的预定流量比例分布。 [0023] In one embodiment, an inhalation system for pulmonary drug delivery, comprising: a dry powder inhaler, the powder inhaler comprises a housing and a mouth portion having an air inlet and an air outlet, in air duct and configured to structurally cartridge receiving opening between the air inlet and the air outlet; slide mounting mechanism, such as a cartridge or the like; cartridge, configured to be suitable for a dry powder inhaler and containing a dry powder medicament for inhalation ; wherein the kit comprises a container and a lid portion having one or more air intake or administration of one or more ports; dry powder inhaler used in the system with respect to the total gas flow delivered to the patient through a predetermined flow rate of a kit the proportion of distribution.

[0024] 在这里所公开的实施例中,干粉吸入系统包括在吸入器中的预定量的流量比例。 [0024] In the embodiments herein disclosed embodiments, the dry powder inhalation system comprises a predetermined amount of flow ratio inhaler. 例如,排出吸入器并进入患者的总流量的约20%至70%的流量比例通过给药口或经过药盒输送,而约30%至80%从吸入器的其他管道产生。 For example, about 20% of the total flow discharged inhaler and into the patient's flow rate ratio to 70% or oral administration and from about 30 to 80% is generated from other channels by passing through the inhaler cartridge conveyed. 而且旁路气流或没有进入并排出药盒的气流可以在吸入器内与排出药盒的给药口的气流再结合、以在排出嘴部之前冲淡、加速并最终解聚流化粉末。 And bypass stream or exhaust gas stream and does not enter the cartridge may be recombined with stream discharge port of the kit is administered in the inhaler, before being discharged to the mouth dilute, accelerate and ultimately depolymerization fluidized powder.

[0025] 在这里所述的实施例中,干粉吸入器设置有相对刚性管道或管道系统以及高流动阻力水平,以最大化粉末药物的解聚和帮助输送。 [0025] In the embodiment described herein, the dry powder inhaler is provided with a relatively rigid conduit or pipe system and high flow resistance levels to maximize the depolymerization and assist in delivery of the powdered medicine. 这里所公开的吸入系统包括管道,其在使用中对气流施加阻力以保持较低的流速,将从吸入器排出的粉末颗粒的较大惯性力减小到最小,以防止在上呼吸道中粉末颗粒的咽喉沉积或撞击,从而使在肺部的颗粒沉积最大化。 Inhalation system disclosed herein comprises a conduit which in use is applied to the resistance to gas flow to maintain a lower flow rate, reduced to a minimum suction from a large inertial force of the powder particles discharged, in order to prevent the powder particles in the upper respiratory tract throat deposition or impact, thereby maximizing the deposited particles in the lungs. 因此,由于吸入器设置有保持不变并且不会被变更的空气管道几何形状,本发明的吸入系统在重复使用后、提供从吸入器排出的有效并且连贯的粉末药物。 Accordingly, since the inhaler is provided with a remain unchanged and will not be changed geometry of the air duct, the suction system of the present invention after repeated use, the discharge from the inhaler to provide efficient and coherent powdered medicament. 在某些实施例中,干粉药物在小于3秒内、或通常小于I秒内从吸入器连贯性地被给出。 In certain embodiments, the dry powder medicament in less than 3 seconds, or generally less than I second are given within a coherent manner from the inhaler. 在某些实施例中,吸入系统具有例如约O. 065到约0.200( V kPa)/liter每分钟的高阻力值。 In certain embodiments, the intake system having a high resistance value, for example, from about O. 065 per minute and about 0.200 (V kPa) / liter. 因此,在吸入系统中,从 Thus, in the intake system, from

2到20kPa的峰值吸入压降产生约7到70升每分钟的峰值流速。 2 to 20kPa, peak inhalation pressure drop from about 7 to 70 liters per minute peak flow. 这些流速导致在I到30mg之间或更大的填充量中的大于75%的药盒含量被给出。 These flow rates lead to I between the amount of 30mg or greater in the filling cartridge content greater than 75% is given. 在某些实施例中,这些性能特征由最终用户在单次吸入动作中实现以产生大于90%的药盒给药比例。 In certain embodiments, these performance characteristics to achieve the ratio of administration to produce a kit of greater than 90% in a single suction action by the end user. 在某些实施例中,吸入器和药盒系统配置成通过作为被输送给患者的连续流从吸入器排出粉末来提供单次剂量。 In certain embodiments, the inhaler and cartridge system is configured to provide a single dose is delivered as a continuous stream through to a patient is discharged from the powder inhaler.

[0026] 在一个实施例中,提供了用于在干粉吸入器中在吸入期间有效地解聚干粉制剂的方法。 [0026] In one embodiment, there is provided a method for depolymerization of a dry powder inhaler in a dry powder formulation during inhalation is efficient. 该方法可包括以下步骤:提供包括容器的干粉吸入器,该容器具有空气入口、与嘴部空气管道连通的给药口,并且装有制剂并将制剂输送给需要制剂的受试者;通过受试者的吸气在吸入器中产生空气流,以使得进入吸入器的气流的约20%到约70%进入并排出容器;允许空气流进入容器进气口、循环并在与给药口垂直的轴线上翻腾制剂以流化制剂,从而产生被流化的制剂;通过给药口并且在空气管道中加速已计量的量的流化制剂,并且在到达受试者之前在吸入器的嘴部管道中使含有流化制剂的空气流减速。 The method may include the steps of: providing a dry powder inhaler includes a container, the container having an air inlet, oral administration of the air duct communicating with the nozzle portion, and with the formulation and preparation to a subject needs formulation; receiving by intake of those tested in the inhaler to generate an air flow, so that the airflow into the inhaler from about 20% to about 70%, and is discharged into the container; allow air to flow into the intake port of the container, perpendicular to the loop and administration port somersault on the axis of the formulation to fluidize the formulation, to produce a fluidized formulation; administered by mouth and accelerates metered amount of fluidizing air duct in the formulation, and before reaching the mouth of the subject in the inhaler the air flow duct containing fluidized formulation manipulation deceleration. 在某些特定实施例中,在药物输送期间,通过吸入器的总流量的20%到60%通过药盒。 In certain embodiments, the drug delivery period, by 20% to 60% of the total flow rate through the inhaler cartridge.

[0027] 在另一实施例中,提供了用于解聚和分散用于吸入的干粉制剂的方法,该方法包括以下步骤:在包括嘴部和容器的干粉吸入器中产生空气流,容器具有至少一个进气口和至少一个给药口,并且装有干粉制剂;容器在至少一个进气口和至少一个给药口之间形成空气通路,并且进气口将进入容器的空气流的至少一部分引导至至少一个给药口;使空气流在与所述至少一个给药口垂直的轴线上在容器内翻腾粉末、以形成空气流药物混合物;以及加速通过至少一个给药口排出容器的空气流。 [0027] In another embodiment, a method for the depolymerization and dispersing a dry powder formulation for inhalation, the method comprising the steps of: generating an air flow in a dry powder inhaler includes a nozzle portion and a container, the container having at least a portion of the container forming an air passage between the at least one air inlet and at least one dosing opening, and the intake port of the air flow into the container; the at least one air inlet opening and at least one administration, and dry powder formulation containing at least one opening directed to be administered; churning air flow on the powder in the container is administered with at least one opening perpendicular to the axis to form an air flow drug mixture; and accelerate the discharge of the container through the administration of at least one air flow opening . 在一个实施例中,吸入器嘴部被配置成具有逐渐增大的横截面、以使气流减速并最小化在吸入器内部的粉末沉积以及促进粉末到患者的最大输送。 In one embodiment, the inhaler mouthpiece is configured to have an increasing cross section, in order to decelerate the air flow and minimize powder deposition maximum suction conveyance device inside the patient and to facilitate powder. 在一个实施例中,例如,吸入器的口腔放置部分的横截面积在约3cm的近似长度上可以从约O. 05cm2到O. 25cm2。 In one embodiment, for example, an oral inhaler is placed on a portion of the cross sectional area of ​​approximately 3cm length may be from about O. 05cm2 to about O. 25cm2. 这些尺寸取决于用于吸入器的粉末的类型和吸入器本身的尺寸。 These dimensions depend on the size for an inhaler and a suction type powder itself.

[0028] 在一个实施例中,提供了用于干粉吸入器的药盒,其包括:药盒顶部和限制内部体积的容器;其中药盒顶部具有在容器上方延伸的下表面;下表面配置成与容器配合,并且包括包含内部体积的区域和将内部体积暴露给环境空气的区域。 [0028] In one embodiment, a kit is provided a dry powder inhaler, comprising: a cartridge top and the interior volume of the container limits; wherein the cartridge has a top surface of the container extending above the lower; a lower surface configured to mating with the container, and includes a region and a region comprising the interior volume of the internal volume is exposed to ambient air.

[0029] 在替换实施例中,提供了用于通过干粉输送设备输送颗粒的方法,该方法包括:将用于保持和分配颗粒的药盒插入到输送设备中,该药盒包括装入颗粒的封装、给药孔和进气孔;其中封装、给药孔和进气孔定位成使得,当进入气体进入进气孔时,颗粒通过如上所述解聚模式中的至少一种被解聚以分离颗粒,并且随同进入气体的一部分的颗粒通过给药孔被给出;同时迫使气体通过与给药孔连通的输送管道,从而使进入气体进入进气孔、解聚颗粒并且随着通过给药孔的进入气体的一部分给出颗粒;以及通过设备的输送管道(例如在吸入器嘴部中)输送颗粒。 [0029] In an alternative embodiment, there is provided a method for transporting particles through a dry powder delivery device, the method comprising: for holding and dispensing cartridge is inserted into the particle delivery device, the kit comprising charged particles, package delivery opening and an intake hole; wherein the package delivery opening and an intake hole positioned such that, when the gas enters into the inlet opening, by at least one particle is depolymerized solution as described above to pattern the poly separate particles, and the particles along with a part of the gas entering the aperture is given by the administration; while forcing a gas through a delivery conduit communicating with the delivery opening so that the gas enters into the inlet hole, and with the depolymerization particles by administration of a portion of the gas entering the aperture is given particles; and the device through the delivery conduit (e.g. in the inhaler in the mouth) transport particles. 在这里所述的实施例中,为了实现粉末解聚、干粉吸入器可在结构上配置并设置有粉末解聚的一个或多个区,其中解聚区在吸入动作期间能够帮助通过进入吸入器的空气流翻腾粉末、含有粉末的空气流的加速、含有粉末的空气流的减速、粉末颗粒的剪切、困在粉末颗粒中的空气的膨胀和/或其组合。 In an embodiment herein in order to achieve depolymerization powder, dry powder inhaler may be configured and provided with one or more regions in the powder structure depolymerization, the depolymerization zone in which the suction action can help during the inhaler through the inlet somersault powder air flow, comprising air flow accelerating the powder, the powder-containing air stream deceleration, cut powder particles, the powder particles trapped in the expansion of the air and / or combinations thereof.

[0030] 在另一实施例中,吸入系统包括呼吸供能的干粉吸入器,装有药物的药盒,其中药物可以例如包括,诸如包括二酮哌嗪和活性剂的化合物等的用于肺部给药的药物制剂。 [0030] In another embodiment, the inhalation system comprises a cartridge energizing breathing dry powder inhaler, containing a drug, wherein the drug may include, for example, as a compound comprising a diketopiperazine and an active agent to the lungs like administration of a pharmaceutical formulation unit. 在某些实施例中,活性剂包括诸如胰岛素、胰高血糖素样肽I、胃泌素调节素、肽YY、醋酸艾塞那肽、甲状旁腺激素、其类似物等的肽和蛋白质、小分子、疫苗等。 In certain embodiments, the active agent include such as insulin, glucagon-like peptide I, gastrin hormone, peptide YY, exendin peptides that acetic acid, parathyroid hormone, its analogues and other peptides and proteins, small molecules, vaccines and so on. 吸入系统可用在例如用于需要局部或全身药物输送的治疗情况的方法中,例如用于治疗糖尿病、糖尿病前期情况、呼吸道感染、骨质疏松症、肺部疾病、疼痛(包括偏头等的头痛)、肥胖症、中枢和周围神经系统状况和障碍、以及诸如疫苗接种等预防性使用。 Inhalation system can be used in case of need, for example, a method for treating systemic or topical drug delivery, for example, for treating diabetes, pre-diabetes, the respiratory tract infection, osteoporosis, pulmonary disease, pain (including migraine headache, etc.) , obesity, central and peripheral nervous system disorders and conditions, such as vaccinations and prophylactic use. 在一个实施例中,吸入系统包括工具包,其包括用于治疗疾病或失调的吸入系统的各个组件中的至少一个。 In one embodiment, the inhalation system comprises a kit, comprising a suction system for treating a disease or disorder of at least one of the individual components.

[0031] 在一个实施例中,通过了用于向受试者的血液流中有效地输送制剂的方法,该方法包括吸入系统,其包括吸入器,该吸入器包括装有制剂的药盒,制剂含有二酮哌嗪,其中吸入系统输送包含二酮哌嗪微粒的粉末羽流,二酮哌嗪微粒具有从约2. 5 μ um到10 μ m的体积中值几何直径(VMGD)。 [0031] In one embodiment, by a method for efficiently transporting the formulation to the blood flow in a subject, the method comprising a suction system, which includes an inhaler, the inhaler comprising a cartridge containing a preparation, formulation comprising a diketopiperazine, wherein the inhalation system comprises diketopiperazine microparticles conveying powder plume, um diketopiperazine microparticles having from about 2. 5 μ to 10 μ m in volume median geometric diameter (VMGD). 在示例实施例中,微粒的VMGD可从约2 μ m到8 μ m。 In an exemplary embodiment, the VMGD microparticles can range from about 2 μ m to 8 μ m. 在示例实施例中,在填充量范围在3. 5mg到IOmg粉末的制剂的单次吸入中,微粒的VMGD可从约4 μ m到7 μ m。 In an exemplary embodiment, the filling of the inhalation formulation in an amount ranging 3. 5mg to IOmg single powder, the particles may be from about VMGD of 4 μ m to 7 μ m. 在该实施例和其他实施例中,吸入系统从药盒输送干粉制剂的90%。 In this embodiment and other embodiments, the suction delivery system cartridge 90% from the dry powder formulation.

[0032] 在另一实施例中,提供了干粉吸入器,其包括:a)嘴部,其配置成通过口腔吸入将干粉输送给受试者;b)容器壳体;c)刚性空气管道,其在容器壳体和嘴部之间延伸并配置成与环境空气连通;其中干粉吸入器被配置成在单次吸入中从定位在容器壳体中的容器、以粉末颗粒排出大于75%的干粉,并且被排出的粉末颗粒具有小于5微米的体积中值几何直径(VMGD),当用户通过嘴部吸入以在2秒内产生约2kPa的峰值压力和至少约I. O、I. I和 [0032] In another embodiment, a dry powder inhaler, comprising: a) the mouth portion, which is configured to deliver powder to a subject by oral inhalation; b) a container housing; c) the rigidity of the air duct, extending between the container and the nozzle housing portion and configured to communicate with the ambient air; wherein the dry powder inhaler is configured in a single inhalation from a container positioned in the housing container, the powder particles are discharged to greater than 75% of dry , and the powder particles are discharged with a volume median geometric diameter of less than 5 microns (a VMGD), when the user through the suction nozzle portion to produce a peak pressure of about 2kPa at least about 2 seconds, and I. O, I. I and

I. 2kPa*sec的压力与时间曲线的I秒内曲线下面积(AUC)。 The area under the curve I I. 2kPa * sec seconds of pressure versus time curve (AUC). 在另一实施例中压力与时间曲线的I秒内AUC在约I. O到约15kPa*sec之间。 I AUC embodiment the second pressure versus time curve in another embodiment between about I. O to about 15kPa * sec.

[0033] 在某些实施例中,还提供了利用高阻力干粉吸入器输送干粉药物剂量的方法,所述方法包括:提供装有一剂干粉药物的高阻力干粉吸入器,并且以足够的力(作用力)从吸入器吸入以在2秒内达到至少2kPa的峰值吸入压力;以及产生至少约I. O、I. I和 [0033] In certain embodiments, a method is also provided with a high resistance dry powder inhaler delivery of dry powder medicament doses, the method comprising: providing a dry powder medicament with high resistance dry powder inhaler, and with sufficient force ( force) sucked from the inhaler to reach the peak of at least 2kPa suction pressure within 2 seconds; and generating at least about I. O, I I and.

I. 2kPa*sec的压力与时间曲线的第I秒中的曲线下面积(AUCch1sJ ;其中大于75%的干粉剂量被以粉末颗粒从吸入器排放或排出。在某些实施例中,被排出颗粒的VMGD小于约5微米。· The area under the curve I, I. 2kPa * sec seconds of pressure versus time curve (AUCch1sJ;. Wherein more than 75% of the dose of dry powder to the powder particles are discharged from the inhaler or discharging In certain embodiments, the particles are discharged VMGD of less than about 5 microns. ·

[0034] 在另一实施例中,利用高阻力干粉吸入器输送充分解聚的干粉药物剂量的方法包括:提供装有干粉药物剂量的高阻力干粉吸入器;以足够的力从吸入器吸入以在2秒内达到至少2kPa的峰值吸入压力;以及产生至少约I. O、I. I和I. 2kPa*sec的吸入压力-时间曲线的第I秒中的曲线下面积(AUCch1sJ ;其中被排出颗粒的VMGD(x50)小于约5微米。在替换实施例中,干粉由具有中值粒径的微粒构成,并且当吸入器被最佳使用时例如约6kPa时,被排出粉末颗粒的VMGD (x50)不大于中值粒径的I. 33倍。 [0034] In another embodiment, a method of using a high resistance dry powder inhaler delivery depolymerized sufficiently dry powder medicament dose comprises: providing a high resistance dry powder inhaler containing a dry powder medicament dose; sufficient inhalation force from the inhaler 2kPa peak suction pressure in at least 2 seconds; and producing at least about I. O, I I I. 2kPa * sec and a suction pressure - the area (AUCch1sJ time curve of the first curve I sec; which is discharged VMGD particles (X50) of less than about 5 microns. in an alternative embodiment, the dry powder consists of particles having a median particle size, and when the inhaler is used, for example, about 6kPa best, the powder particles discharged VMGD (X50 ) I. median particle size of not more than 33 times.

[0035] 在另一实施例中,描述了为了输送干粉的高阻力干粉吸入器的使用,其中干粉吸入器具有从约0.065( V kPa)/liter每分钟到约O. 200 ( V kPa)/liter每分钟范围的空气流阻力值,并且装有一剂干粉,其中施加足够的力以在2秒内达到至少2kPa的峰值吸入压力;并且其中产生了至少约I. O、I. I和I. 2kPa*sec的吸入压力与时间曲线的第I秒中的曲线下面积(AUCch1sJ ;并且其中大于75%的干粉剂量被以粉末颗粒从吸入器排放或排出。 [0035] In another embodiment, there is described the delivery of a dry powder to a high resistance dry powder inhaler, wherein the dry powder inhaler having from about 0.065 (V kPa) / liter to about O. 200 (V kPa) per minute / air-flow resistance value liter per minute range, and is provided with a dry powder, wherein applying sufficient force to achieve a peak of at least 2kPa suction pressure within 2 seconds; and wherein generating at least about I. O, I I, and I.. 2kPa * sec area of ​​the suction pressure versus time curve of the second curve section I (AUCch1sJ; and wherein the dry powder dose is greater than 75% of the particles discharged from a powder inhaler or discharged.

[0036] 在某些实施例中,这里所述的吸入系统被用于利用所述药物、治疗需要这里所述的疾病或失调治疗的患者。 [0036] In certain embodiments, the inhalation system described herein is the use of drugs for treating a disease or disorder patient in need of treatment described herein.

[0037] 在又一实施例中,描述了用于向患者输送干粉药物的高阻力干粉吸入器,其特征在于,设置了干粉吸入器,其具有从约0.065( V kPa)/liter每分钟到约0.200( V kPa)/liter每分钟范围的空气流阻力值,并且装有一剂干粉药物,其中在使用时施加足够的力以在2秒内达到至少2kPa的峰值吸入压力;并且其中产生了至少约I. 0,1. I和I. 2kPa*sec的吸入压力与时间曲线的第I秒中的曲线下面积(AUCch1sJ ;并且其中大于75%的干粉剂量被以粉末颗粒从吸入器排放或排出。 [0037] In yet another embodiment, there is described a high resistance dry powder inhaler for delivering a dry powder medicament to a patient, characterized in that a dry powder inhaler, having from about 0.065 (V kPa) / liter per minute about 0.200 (V kPa) / liter of air-flow resistance value range per minute, and is provided with a dry powder medicament, wherein sufficient force is applied during use to reach a peak at least 2kPa within 2 seconds suction pressure; and wherein generating at least I. 0,1 about area under the curve I in the first and second I I. 2kPa * sec suction pressure versus time curve (AUCch1sJ;. and wherein the dry powder dose greater than 75% is discharged or exhausted from the particles in a powder inhaler .

[0038] 在另一实施例中,设置了吸入系统,其包括吸入器、装有包括二酮哌嗪微粒的、用于输送到全身血液循环的干粉制剂的药盒;其中二酮哌嗪微粒输送血浆水平(暴露量)为每毫克在单次吸入中排出的二酮哌嗪、AUCQ_2to在1,300ng*min/mL和3,200ng*min/mL之间的二酮哌嗪。 [0038] In another embodiment, the inhalation system is provided, comprising an inhaler, comprising diketopiperazine microparticles containing the kit dry powder formulation for delivery to the systemic blood circulation; wherein diketopiperazine microparticles conveying plasma level (exposure amount) per mg of diketopiperazine discharged in a single inhalation, AUCQ_2to diketopiperazine between 1,300ng * min / mL and 3,200ng * min / mL of. 在另一示例性实施例中,吸入系统设置有吸入器、装有包括二酮哌嗪微粒的、用于输送到全身血液循环的干粉制剂的药盒;其中二酮哌嗪微粒输送血浆水平(暴露量)为每毫克单次吸入中排出的粉末AUCQ_2hr大于2,300ng*min/mL的二酮哌嗪。 In another exemplary embodiment, the suction system is provided with an inhaler, equipped kit dry powder formulation comprising a diketopiperazine microparticles for delivery to the systemic blood circulation; diketopiperazine microparticles wherein the conveying plasma levels ( exposure) is discharged from the powder AUCQ_2hr single inhalation per mg greater than 2,300ng * min / mL of diketopiperazine. 在这些实施例的方面中,DKP是FDKP。 In aspects of these embodiments, DKP is FDKP. 在该实施例和其他实施例中,如通过肺部功能测试所评估的以及一秒钟用力呼气量(FEVl)所测量的,二酮哌嗪微粒不造成肺功能下降。 In this embodiment and other embodiments, as assessed by pulmonary function tests, and forced expiratory volume in one second (FEVl) measured, diketopiperazine microparticles do not cause decline in lung function. 在某些实施例中,在受试者中的所测量的FDKP的血浆暴露量可以是每毫克在单次吸入中排出的FDKP粉末、大于2,500ng*min/mL。 In certain embodiments, the plasma FDKP in a subject the measured exposure per mg FDKP powder may be discharged in a single inhalation, greater than 2,500ng * min / mL. 在替换实施例中,所测量的血浆暴露量——受试者的FDKP的AUCchoo可以是每毫克在单次吸入中排出的FDKP粉末大于3,000ng*min/mL。 Plasma In an alternative embodiment, the measured exposure - AUCchoo subject of FDKP per mg FDKP powder may be discharged in a single inhalation greater than 3,000ng * min / mL. 在又一实施例中,在受试者中的FDKP的AUCQ_的所测量血浆暴露量可以是每毫克在包含FDKP的干粉合成物的单次吸入中排出的FDKP、小于或约为5,500ng*min/mL。 In yet another embodiment, AUCQ_ FDKP in a subject of the measurement of plasma exposure may be discharged in a single inhalation per milligram of dry powder composition comprising FDKP of the FDKP, or less than about 5,500ng * min / mL. 在某些实施例中,所记录的暴露量水平表示个体的暴露量。 Exposure levels in certain embodiments, the representation of the recorded exposure of the subject. 在替换实施例中,所记录的暴露量水平表示平均暴露量。 Exposure levels in alternative embodiments, the record represents an average exposure. 包括含量和暴露量的活性剂的数量或者可以活性单位或质量单位表示。 Including the number and content of the active agent exposure or may represent the active units or mass units.

[0039] 在这些和其他的实施例中,微粒还可以包括活性成分。 [0039] In these and other embodiments, the particles may further comprise an active ingredient. 在特定实施例中,活性成分是胰岛素。 In a particular embodiment, the active ingredient is insulin. 在其他示例性实施例中,设置了吸入系统,其包括吸入器、装有包括二酮哌嗪微粒的、用于向全身血液循环输送的干粉制剂的药盒,二酮哌嗪微粒含有胰岛素;其中二酮哌嗪输送每单位在单次吸入中排出的粉末制剂中的胰岛素、AUCV2to大于160 μ U*min/mL的血浆水平(暴露量)的胰岛素。 In other exemplary embodiments, the intake system is provided, comprising an inhaler, containing microparticles comprising a diketopiperazine, a kit for dry powder formulation delivered to the systemic circulation, diketopiperazine microparticles containing insulin; wherein the diketopiperazine discharged per unit conveying powder formulation in a single inhalation of insulin, AUCV2to greater than 160 μ U * min / mL of plasma level (exposure amount) of insulin. 在该实施例的方面中,吸入系统被配置成输送并获得如下血浆水平或暴露量,其中每单位在单次吸入中排出的粉末制剂中的胰岛素、所测量的胰岛素AUCV2to范围是从约100到约1,000 μ U*min/mL。 In aspects of this embodiment, the inhalation system is configured to deliver and obtain the following plasma levels or exposure, wherein the powder formulation per discharged in a single inhalation of insulin, measured insulin AUCV2to range is from about 100 to about 1,000 μ U * min / mL. 在某些实施例中,所记录的暴露量水平代表个体暴露量。 Exposure levels in certain embodiments, the individual representative of recorded exposure. 在替换实施例中,所记录的暴露量水平是平均暴露量。 In an alternative embodiment, the exposure level is recorded average exposure.

[0040] 在另一示例性实施例中,提供了吸入系统,其包括吸入系统,其包括吸入器、装有包括二酮哌嗪微粒的、用于向全身血液循环输送的干粉制剂的药盒,二酮哌嗪微粒含有胰岛素;其中二酮哌嗪输送每单位在单次吸入中排出的粉末制剂中的胰岛素、AUCV2to大于100 μ U*min/mL的血浆水平(暴露量的)胰岛素。 [0040] In another exemplary embodiment, there is provided a suction system including a suction system, which comprises a suction device, comprising diketopiperazine microparticles containing the kit formulation for a dry powder delivered to the systemic blood circulation , diketopiperazine microparticles containing insulin; diketopiperazine wherein the conveying powder formulation is discharged per unit in a single inhalation of insulin, AUCV2to greater than 100 μ U * min / mL of plasma level (exposure amount) of insulin. 在该实施例的方面中,吸入系统被配置成向患者输送如下胰岛素和二酮哌嗪的制剂,其得到具有在每单位在单次吸入中排出的被填充药物的胰岛素、100至200 μ U*min/mL范围的被测量AUCV4hr的胰岛素的血浆暴露量。 In aspects of this embodiment, the inhalation system is configured to formulation as a diketopiperazine and insulin delivered to the patient, which has been filled to give the insulin of drug per unit discharged in a single inhalation of from 100 to 200 μ U * min / mL insulin AUCV4hr range to be measured of plasma exposure. 在这些实施例的方面中,AUCV4hr可以是大于每单位在单次吸入中排出的被填充的胰岛素110、125、150或175 μ U*min/mL。 In aspects of these embodiments, AUCV4hr may be greater than the discharge per unit insulin filled in a single inhalation 110,125,150 or 175 μ U * min / mL. 在这些和其他实施例中,制剂的胰岛素含量包括从制剂的约10到约20% (w/w) ο In these and other embodiments, the insulin formulation comprises ο content from about 10 to about 20% of the formulation (w / w)

[0041] 在另一示例性实施例中,通过了吸入系统,其包括吸入系统,其包括吸入器、装有包括二酮哌嗪微粒的、用于向全身血液循环输送的干粉制剂的药盒,二酮哌嗪微粒含有胰岛素;其中儿童哌嗪微粒在服药的30分钟内每mg在单次吸入中排出的粉末输送Cniax大于10 μ U/mL的胰岛素血浆水平。 [0041] In another exemplary embodiment, the inhalation system, comprising a suction system, which comprises a suction device, with particles comprising diketopiperazine, dry powder formulations for delivery to the systemic circulation of a kit , diketopiperazine microparticles containing insulin; wherein the piperazine children medication particles per mg of powder discharge in a single inhalation delivery over 30 minutes Cniax greater than 10 μ U / mL of plasma levels of insulin. 在本实施例的方面中,每毫克在单次吸入中排出的粉末并且在服药后的30分钟内,所服用的胰岛素制剂产生从约10到20yU/mI^^Cmax。 In aspects of this embodiment, the powder discharged per mg in a single inhalation and within 30 minutes after dosing, the administered insulin preparations produced from about 10 to 20yU / mI ^^ Cmax. 在该实施例的另一方面中,可在服药的25、20或15分钟内得到胰岛素的C_。 In another aspect of this embodiment, the insulin is available in the medication C_ 25, 20 or 15 minutes. 在这些Cniax实施例的替换实施例中,在制剂的肺部吸入后得到的Cmax是每单位填充在药盒中的胰岛素大于3 μ U/mL,或者是在每单位在药盒剂量中的胰岛素3到6或4到6 μ U/mL的范围。 In these alternative embodiments Cniax embodiments, the lungs after inhalation formulation Cmax obtained in the kit is filled per unit of insulin is greater than 3 μ U / mL, or insulin per unit dose in the cartridge the range of 3 to 6 or 4 to 6 μ U / mL of.

[0042] 在另一实施例中,提供了吸入系统,其包括:干粉吸入器;以及包括二酮哌嗪的多个粉末微粒的干粉制剂,其中吸入系统被配置成将二酮哌嗪输送到受试者的肺循环,并且二酮哌嗪可以在受试者的血浆中被测量为具有平均暴露量或者每毫克在单次吸入中所服药的干粉制剂中的二酮哌嗪含量、AUCchoo大于2,300ng*min/mL。 [0042] In another embodiment, an inhalation system, comprising: a dry powder inhaler; and dry powder formulations comprising diketopiperazine plurality of powder particles, wherein the inhalation system is configured to deliver to the diketopiperazine pulmonary circulation of the subject, and a diketopiperazine may be measured as having an average exposure or diketopiperazine content per mg dry powder formulation in a single inhalation of the medication, AUCchoo greater than 2 in the plasma of the subject , 300ng * min / mL. 在一个实施例中,吸入系统还包括配置成适用于呼吸供能的干粉吸入器的药盒。 In one embodiment, the inhalation system comprises a further cartridge configured to be suitable for breathing can dry powder inhaler. 在该实施例和其他实施例中,在制剂中的二酮哌嗪是二次_3,6- (N-延胡索酰-4-氨基丁基)-2,5- 二酮哌嗪(FDKP)。 In this embodiment and other embodiments, the diketopiperazine in the formulation is a secondary _3,6- (N- fumaric acid-4-amino-butyl) -2,5-diketopiperazine (the FDKP) .

[0043] 在其中在制剂中使用FDKP的实施例中,系统能够以小于I小时的Tmax将FDKP输送到全身血液循环中。 [0043] In embodiments where FDKP in the formulation, the system can be less than I hour Tmax FDKP delivered to the systemic blood circulation. 在某些实施例中,在单次吸入中服药FDKP之后、FDKP的Tmax可以小于15或30分钟。 In certain embodiments, after taking in a single inhalation FDKP, FDKP can Tmax of less than 15 or 30 minutes. 在该实施例和其他实施例中,从O到2小时、O到4小时或O到无穷测量了AUC。 In this embodiment and other embodiments, from O to 2 hours, 4 hours, or O to O to infinity was measured AUC.

[0044] 在另一实施例中,提供了吸入系统,其包括呼吸供能的吸入器和包括多个二酮哌嗪颗粒的干粉制剂;其中吸入系统可操作地配置为排出包括二酮哌嗪微粒的粉末羽流,其中二酮哌嗪微粒具有从2 μ m到8 μ m范围的体积中值几何直径和小于4 μ m的几何标准偏差。 [0044] In another embodiment, an inhalation system comprising a breathing and energized dry powder inhaler formulation comprising a plurality of diketopiperazine particles; wherein the inhalation system is operably configured to discharge a diketopiperazine comprising fine powder plume, wherein the diketopiperazine microparticles having a geometric diameter and geometric standard deviation of from 2 μ m to a median volume is less than 8 μ m range of 4 μ m.

[0045] 在一个实施例中,提供了用于药物的肺部输送的吸入系统,其包括呼吸供能的吸入器和包括多个二酮哌嗪颗粒的干粉制剂;其中吸入系统可操作地配置成在粉末制剂的一次吸入后排出大于90%的粉末颗粒,粉末颗粒在小于30分钟或小于25分钟的时间内溶解并被吸收到血液中,产生二酮哌嗪的峰值浓度。 [0045] In one embodiment, an inhalation system for pulmonary delivery of drugs, including respiratory and energized dry powder inhaler formulation comprising a plurality of diketopiperazine particles; wherein the inhalation system is operably arranged after a discharge to suction powder formulation more than 90% of the powder particles, the powder particles are dissolved and absorbed into the blood in less than 30 minutes or less than 25 minutes, it produces a peak concentration of diketopiperazine. 在某些实施例中,系统在单次吸入中排出大于95%的粉末颗粒,其中颗粒被吸入到血液循环中。 In certain embodiments, the system is discharged in a single inhalation greater than 95% of the powder particles, wherein the particles are sucked into the blood circulation. [0046] 在一个实施例中,提供了吸入系统,其包括干粉吸入器;以及包括多个粉末颗粒的干粉制剂,其中粉末颗粒包括胰岛素;其中吸入系统被配置成将胰岛素输送到受试者的肺循环,并且测量了在受试者的血浆中的胰岛素,其具有每单位在单次吸入中所服用的干粉制剂中的胰岛素、大于160uU*min/mL的平均AUCch21^ [0046] In one embodiment, an inhalation system comprising a dry powder inhaler; and a dry powder formulation comprising a plurality of powder particles, wherein the powder particles comprise insulin; wherein the inhalation system is configured to deliver insulin to the subject pulmonary circulation, and the plasma insulin was measured in the subject, each unit having in a dry powder formulation in a single inhalation of the administered insulin, greater than 160uU * min / average AUCch21 mL of ^

[0047] 在一个实施例中,提供了吸入系统,受试者通过口腔吸入服用干粉制剂,并且制剂包括胰岛素的粉末颗粒,该粉末颗粒可将胰岛素输送到受试者的全身血液循环,其中胰岛素的Cmax在单次吸入中给予患者之后小于30分钟以内测量。 [0047] In one embodiment, an inhalation system, subject by oral inhalation administration of dry powder formulations, and the formulations include insulin powder particles, the powder particles can deliver insulin to the blood circulation of the subject, wherein the insulin Cmax after administration of a single patient inhalation measured within less than 30 minutes.

[0048] 在实施例中,提供了吸入系统,其包括:呼吸供能的干粉吸入器,以及包括多个二酮哌嗪颗粒的粉末制剂;其中吸入系统可操作地配置成排出包括二酮哌嗪微粒的粉末羽流,二酮哌嗪微粒具有从2 μ m到8 μ m范围的体积中值几何直径和小于4 μ m的几何标准偏差。 [0048] In an embodiment, an inhalation system, comprising: energizing breathing dry powder inhaler, and a powder formulation comprising a plurality of diketopiperazine particles; wherein the inhalation system is operably configured to discharge a diketopiperazine comprising piperazine fine powder plume, diketopiperazine microparticles having a geometric diameter and geometric standard deviation of from 2 μ m to a median volume is less than 8 μ m range of 4 μ m.

[0049] 在又一实施例中,提供了用于药物的肺部输送的吸入系统,包括:呼吸供能的干粉吸入器,包括多个二酮哌嗪颗粒的粉末制剂;其中吸入系统可操作地配置成排出粉末颗粒,该粉末颗粒被吸收到血液中、以在小于等于30、25、20或15分钟内产生药物的峰值浓度。 [0049] In yet another embodiment, an inhalation system for pulmonary drug delivery, comprising: energizing breathing dry powder inhaler, comprising a plurality of powder formulation of diketopiperazine particles; wherein the inhalation system is operable arranged to discharge the powder particles, the powder particles are absorbed into the bloodstream to produce a peak concentration of the drug within 15 minutes or less 30,25,20.

[0050] 在一个实施例中,干粉吸入器包括配置成通过口腔吸入向受试者输送干粉的嘴部、配置成保持干粉的容器、以及在容器和嘴部之间延伸并配置成与环境空气连通的空气管道,其中干粉吸入器配置成在单次吸入中以粉末颗粒排出大于75%的干粉,并且被排出的粉末颗粒具有小于5微米的体积中值几何直径,当用户通过嘴部吸入以在两秒内产生大于2kPa的峰值吸入压力、以及至少约I. 0,1. I或I. 2kPa*sec的吸入压力与时间曲线的AUCO-Isec ;其中大于75%的干粉剂量作为粉末颗粒从吸入器中被排放或排出。 [0050] In one embodiment, the dry powder inhaler including a dry powder delivery unit configured to subject the mouth by oral inhalation, the powder container configured to hold and configured to extend between the container and the ambient air in the nozzle portion communicating the air duct, wherein the dry powder inhaler configured to powder particles discharged powder greater than 75% in a single inhalation, and the powder particles discharged having a median volume of less than 5 microns geometric diameter, when the user through the mouth inhalation is generated in two seconds 2kPa suction pressure greater than a peak, and at least about or I. 0,1 I I. 2kPa * sec suction pressure versus time curve AUCO-Isec;. wherein more than 75% of the particles as a powder from a dry powder dose It is discharged or exhausted inhaler.

[0051] 在又一实施例中,公开了用于利用高阻力干粉吸入器向受试者输送一剂干粉药物的方法,该方法包括以下步骤:提供具有从约0.065( V kPa)/liter每分钟到约O. 200 ( V kPa)/liter每分钟的范围的流动阻力值的干粉吸入器;以足够的力从吸入器中吸入,以在2秒内达到至少2kPa的峰值吸入压力;以及产生至少约I. O、I. I或I. 2kPa*sec的吸入压力与时间曲线的AUC0_lsec ;其中大于75%的干粉剂量作为粉末颗粒从吸入器中被排放或排出。 [0051] In yet another embodiment, a method is disclosed for utilizing the high resistance dry powder inhaler conveying a dry powder medicament to a subject, the method comprising the steps of: providing a range from about 0.065 (V kPa) / liter per minutes to about O. 200 (V kPa) / liter dry powder inhaler flow resistance value range per minute; a sufficient force drawn from the inhaler to reach a peak of at least 2kPa suction pressure within 2 seconds; and generating at least about I. O, I AUC0_lsec I I. 2kPa * sec or suction pressure versus time curve;. wherein more than 75% of the dry powder dose is discharged as a powder or granules discharged from the inhaler. 附图说明 BRIEF DESCRIPTION

[0052] 图I描述了在吸入系统中使用的吸入器的示例实施例,示出了在关闭配置中的吸入器的等距视图。 [0052] Figure I depicts an example of the inhaler used in an inhaler system embodiment, shown in isometric view in the closed configuration inhaler.

[0053] 图2、3、4、5和6分别描述了图I的吸入器的侧视图、俯视图、底视图、近端和远端视图。 [0053] FIG, 4, 5 and 6 depict a side view of the inhaler of Figure I, a plan view, a bottom view, a proximal end and a distal end view.

[0054] 图7描述了在打开配置下的包括图I的吸入器的吸入系统的实施例的立体图,示出了相应的药盒和嘴部盖。 [0054] FIG. 7 depicts a perspective view of an embodiment in the open configuration of Figure I comprises a suction system of the inhaler, showing cartridge and a corresponding lid mouth.

[0055] 图8描述了以通过中间纵轴的截面的、带有安装在保持器中的药盒的、在打开配置下的图6的吸入器的等轴视图。 [0055] FIG 8 depicts an isometric view of a cross-section through the longitudinal axis of the intermediate with a cartridge mounted in the holder, in the open configuration of FIG inhaler 6. [0056] 图9描述了处于关闭状态的吸入器以及处于配药状态的药盒。 [0056] Figure 9 depicts the inhaler is in the closed state and the state of dispensing cartridge.

[0057] 图10图示了在打开配置下的吸入器、干粉吸入系统的替换实施例的立体图,示出了可安装在吸入器中的对应的药盒的类型和取向。 [0057] FIG. 10 illustrates the inhaler in the open configuration, a perspective view of an alternative embodiment of a dry powder inhaler system showing the type and orientation of the corresponding cartridge may be installed in the inhaler.

[0058] 图11描述了在打开位置的图10的干粉吸入器的等轴视图。 [0058] FIG 11 depicts an isometric view of a dry powder inhaler in the open position of FIG. 10.

[0059] 图12图示了示出了吸入器组成部分的图48的吸入器的分解图。 [0059] FIG. 12 illustrates the composition of the inhaler is shown an exploded view of a portion of the inhaler 48 of FIG.

[0060] 图13图示了在打开配置下的图10的吸入器的立体图,并且示出了安装在吸入器中的药盒。 [0060] FIG. 13 illustrates a perspective view in an open configuration the inhaler of Figure 10, and shows a cartridge installed in the inhaler.

[0061] 图14示出了图12所描述的吸入器的中间纵向截面图,其示出了在保持配置中并且与滑板接触的药盒容器,并且齿轮机构与滑板接触。 [0061] FIG. 14 shows a longitudinal sectional view of FIG. 12 intermediate the inhaler described, showing a cartridge in the holding vessel configuration and in contact with the slide, and the gear mechanism in contact with the slide plate.

[0062] 图15图示了在关闭配置中的图10的吸入器的立体图,并且在吸入器中具有药盒。 [0062] FIG. 15 illustrates a perspective view of the inhaler in the closed configuration in Figure 10 and has a cartridge in the inhaler.

[0063] 图16图示了图53所描述的吸入器的中间纵向截面图,其示出了在给药配置中的药盒容器以及通过容器建立的空气流动通路。 [0063] FIG. 16 illustrates a longitudinal cross-sectional view of the intermediate FIG. 53 described inhaler, showing a cartridge in the container and the dosing configuration an air flow path through the vessel created.

[0064] 图17图示了用于图I的吸入器的药盒实施例的立体图,并且描述了在保持配置中的药盒。 [0064] FIG 17 illustrates a perspective view of a cartridge of FIG. I inhaler embodiment, and the description of the cartridge in the holding configuration.

[0065] 图18图示了图17的药盒实施例的俯视图,其示出了药盒上表面的组成结构。 [0065] FIG. 18 illustrates a top view of the embodiment of the cartridge of FIG. 17, which shows the composition of the surface structure of the cartridge.

[0066] 图19图示了图17的药盒实施例的底视图,其示出了药盒下表面的组成结构。 [0066] FIG. 19 illustrates a bottom view of the embodiment of the cartridge of FIG. 17, which shows the composition of the structure of the lower surface of the cartridge.

[0067] 图20图示了纵向截面和在保持配置下的图17的药盒示例的立体图。 [0067] FIG. 20 illustrates a perspective view of an example of a kit in a longitudinal section and FIG. 17 of the holding configuration.

[0068] 图21图示了纵向截面和在给药配置下的图17的药盒示例的立体图。 [0068] FIG. 21 illustrates a perspective view of an example of a kit in a longitudinal section and FIG. 17 arranged administration.

[0069] 图22描述了在保持配置中的药盒的替换实施例的立体图。 [0069] FIG. 22 depicts a perspective view of an embodiment of the alternative holding arrangement in a kit.

[0070] 图23到图27分别以俯视图、底视图、近端视图、远端视图和侧视图描述了图22所示的药盒实施例。 [0070] FIGS. 23 to 27 are respectively a top view, a bottom view, a proximal end view, and side views of a distal end of the cartridge described embodiment shown in FIG. 22.

[0071] 图28描述了在给药配置下的图22中所示的药盒实施例的立体图。 [0071] Figure 28 depicts the cartridge shown in FIG. 22 in the dosing configuration in a perspective view of an embodiment.

[0072] 图29和30分别是通过图22和图28的药盒实施例的纵轴的截面图。 [0072] Figures 29 and 30 are longitudinal cross-sectional view through the embodiment of FIGS. 22 and cartridge 28 of FIG.

[0073] 图31是如通过箭头所示的、在干粉吸入器的粉末保持区域内的气流的运动的示意性表示。 [0073] FIG. 31 is as shown by an arrow, showing a schematic air flow in the region of the holding motion of the powder dry powder inhaler.

[0074] 图32是如通过箭头所示的、示出了通过吸入器的气流的流动通路和流动方向的干粉吸入器的实施例的示意性表示。 [0074] FIG. 32 is, as shown by the arrows, is shown by the exemplary embodiment represented in the flow path of the inhaler and the air flow dry powder inhaler flow direction.

[0075] 图33图示了针对示例性实施例的吸入器的流动阻力,基于伯努利远离的流速和压力关系的测量结果的图表。 [0075] FIG. 33 illustrates a flow resistance of an inhaler for the exemplary embodiment, the graph based on the measurement results of the relationship between flow rate and pressure of the Bernoulli away.

[0076] 图34描述了使用吸入器和装有用于吸入的干粉制剂的药盒、利用激光衍射装置得到的粒径分布,其中干粉制剂包括胰岛素和延胡索酰二酮哌嗪颗粒。 [0076] FIG. 34 depicts a cartridge with the use of inhalers and dry powder formulations for inhalation, the particle distribution obtained by laser diffraction apparatus, wherein the dry powder insulin formulation comprising a diketopiperazine and fumaric acid granules.

[0077] 图35描述了根据对示例吸入系统(DPI 2)和MEDTONE® (MTC)进行的所有测试的平均值获得的数据的图形表示,其示出了来自不同药盒粉末含量的、从吸入系统排出的颗粒的累积几何粒径分布。 [0077] FIG. 35 depicts a graphical example of the average of all tests inhalation system (DPI 2) and MEDTONE® (MTC) for the representation of data obtained, which is shown from different levels of the powder cartridge, the suction geometric diameter cumulative distribution of the particles discharged from the system.

[0078] 图36描述了利用没有(曲线A)和有(曲线B)粉末制剂的示例性吸入系统、由受试者进行的并且利用吸入检测系统的吸入记录的图表。 [0078] FIG 36 describes the use without (curve A) and exemplary suction system (curve B) powder formulation of the subject by the use of an inhaler and a suction chart recording detection system.

[0079] 图37是对于吸入含有FDKP微粒之后的6小时、从与图36相同的受试者抽取的样本的血浆中的FDKP的浓度的图表。 [0079] FIG. 37 is a plasma concentration for 6 hours after inhalation comprising FDKP microparticles, extracted from FIG. 36 of the same subject in the sample graph of FDKP. [0080] 图38是根据剂量分组的胰岛素浓度随时间变化的图表。 [0080] FIG. 38 is a dose packet insulin concentration change with time graph.

[0081] 图39是根据剂量分组的FDKP浓度随时间可变化的图表。 [0081] FIG. 39 is a dose packet FDKP concentration may vary with time chart.

[0082] 图40是在研究中的各个个体的血糖偏移的图表。 [0082] FIG. 40 is a graph of blood glucose offset each individual in the study.

[0083] 图41是使用时的本发明设备的示例吸入概况,示出了在两秒内的峰值吸入压力。 [0083] FIG. 41 is an example of the present invention when using the device before inhalation, shows a peak in the intake pressure within two seconds.

[0084] 图42是示出了本发明的吸入器的性能标准的示例吸入器的图表。 [0084] FIG. 42 is a diagram illustrating an example of performance criteria of the present invention, the inhaler graph inhaler.

具体实施方式 Detailed ways

[0085] 这里所公开的一般地是干粉吸入器、用于干粉吸入器的药盒和用于经由肺吸入向病人输送一种或多种制药药物的吸入系统。 [0085] Generally disclosed herein is a dry powder inhaler, a cartridge and a dry powder inhaler to deliver one or more patient via pulmonary inhalation pharmaceutical drug inhalation system. 在一个实施例中,吸入系统包括呼吸供能的干粉吸入器和装有药物制剂的药盒,该药物制剂包含药物活性物质或活性成分和药用载体。 In one embodiment, the inhalation system comprises a dry powder inhaler and a cartridge containing a pharmaceutical formulation breathing energized, the pharmaceutical formulation comprising a pharmaceutically active substance or active ingredient and a pharmaceutically acceptable carrier. 干粉吸入器被设置为各种形状和尺寸,并且可重复使用或供一次性使用、易于使用、制造成本低廉,并且能够使用塑料或其他可接受的材料以简单的步骤大量生产。 Dry powder inhaler is provided in various shapes and sizes, and may be reusable or single-use, easy to use, inexpensive to manufacture, and can be plastic or other materials acceptable for mass production in a simple step. 除了完整的系统,吸入剂、填满的药盒和空药盒构成本文所公开的其他实施例。 In addition to complete systems, inhalers, filled and empty cartridge kits configuration other embodiments disclosed herein. 本吸入系统可以设计为使用任意类型的干粉。 The present inhalation system can be designed with any type of dry powder. 在一个实施例中,干粉是需要最佳解聚条件的相对粘性粉末。 In one embodiment, the dry powder is the best solution polymerization conditions require relatively viscous powder. 在一个实施例中,吸入系统提供了与装有预计量剂量的干粉制剂的一次性药盒相结合的、可重复使用的微型呼吸供能吸入器。 In one embodiment, the inhalation system provides a dry powder dosage formulation and the amount of expected disposable cartridge containing a combination of micro respiratory energizing reusable inhaler.

[0086] 还公开了用于向全身血液循环有效和连贯地输送药物制剂的方法。 [0086] Also disclosed are methods for the efficient blood circulation and consistent delivery of the drug formulation.

[0087] 本文所使用的术语“单位剂量吸入器”是指,适于容纳干粉制剂的一次性容器并且通过吸入从容器向用户输送单次剂量的干粉制剂的吸入器。 [0087] As used herein, the term "unit dose inhaler" means a disposable container adapted to receive a dry powder formulation and a dry powder formulation by inhalation, the inhaler is a single dose delivered from the container to a user. 应该明白,在某些情况下将需要多个单位剂量以提供给用户指定的剂量。 It should be understood that, in some cases, will require more unit doses to provide to the user-specified dose.

[0088] 本文所使用的术语“多次剂量吸入器”指的是具有多个容器的吸入器,每个容器包括预计量剂量的干粉药物,并且吸入器在任何时刻通过吸入输送单次剂量的药物粉末。 [0088] As used herein, the term "multiple-dose inhaler" refers to an inhaler having a plurality of containers, each container comprising a dosage amount of dry powder medicament are expected, and the inhaler at any time a single dose delivery by inhalation medicament powder.

[0089] 本文所使用的“容器”是配置成保持或容纳干粉制剂的封装——装有粉末的封装,并且可以是有盖或无盖的结构。 [0089] "container" as used herein is a package configured to hold or contain a dry powder formulation - the package containing the powder, and can be covered or uncovered structure. 该容器可以与吸入器分开设置,或者可以在结构上结合到吸入器内(例如,不可拆卸的)。 The container may be provided separately from the inhaler, or may be incorporated into the inhaler (e.g., not removable) in structure. 此外,该容器可以被填满干粉。 In addition, the container may be filled powder. 药盒也可以包括容器。 The kit may also comprise a container.

[0090] 本文所使用的“粉末团”指的是具有不规则的诸如宽度、直径和长度之类的几何尺寸的粉末颗粒的块或团。 [0090] As used herein, "powder group" refers to such a width, a block or group of powder particles of a diameter and geometry or the like having a length irregular.

[0091] 本文所使用的术语“微粒”指的是不考虑精确的外部或内部结构、直径约O. 5至约1000 μ m的颗粒。 [0091] As used herein, the term "microparticle" refers Regardless of the precise exterior or interior structure, a diameter of about O. 5 to about 1000 μ m particles. 然而,对于肺部给药,通常需要小于10 μ m的颗粒,尤其是直径的平均颗粒尺寸小于约5. 8 μ m的颗粒。 However, for pulmonary delivery, typically require particles of less than 10 μ m, especially an average particle size diameter of less than about 5. 8 μ m particles.

[0092] 本文所使用的“刚性空气导管”指的是与贯穿吸入系统的空气的通路相关联的、几何形状不改变或保持不变的空气导管,例如,在可重复使用的吸入器中,空气导管在重复使用后保持不变。 [0092] As used herein, "rigid air conduit" refers associated with the passage through the air intake system, the geometry does not change or remain the same air duct, for example, the inhaler may be reusable, air duct remain unchanged after repeated use. 刚性空气导管可以与嘴部、容器、吸入器壳体、容器、容器壳体等相关联。 Rigid air conduit associated with the mouth, the container, the inhaler housing, container, housing, etc. may be associated with the container.

[0093] 本文所使用的“单位剂量”指的是用于吸入的预计量干粉制剂。 [0093] As used herein, "unit dose" refers to an estimated amount of the dry powder formulation for inhalation. 或者,单位剂量可以是具有可以被作为已计量的单次量通过吸收输送的多次制剂的一次性容器。 Alternatively, the unit dosage may be a disposable container having a plurality of times as the formulation may be single dose metered delivery by absorption. 单位剂量药盒/容器装有单次剂量。 Unit dose kit / container filled with a single dose. 或者其可以包括多个单独进入的室,每个室装有单位剂量。 Or it may comprise a plurality of separate entry chamber, each chamber housing a unit dose.

[0094] 本文所使用的术语“约”用来指示包括所采用的设备或方法的误差的标准偏差以确定值的值。 [0094] As used herein, the term "about" is used to indicate the standard error of the apparatus or method includes employed to determine the value of deviation. ·[0095] 本设备可以通过若干方法制造,然而,在一个实施例中,吸入器和药盒是利用包括聚丙烯、环烯烃(cyclicolephin)共聚物、尼龙、诸如聚乙烯之类的聚酯和其他相容的聚合物等的各种类型的塑料材料,通过注塑成型技术、热成型来制造的。 * [0095] The present device may be manufactured by several methods, however, in one embodiment, is the use of the inhaler and cartridge include polypropylene, cycloolefin (cyclicolephin) copolymer, nylon, polyesters such as polyethylene and Various types of plastic material such as other compatible polymers by injection molding techniques, thermoforming manufactured. 在某些实施例中,干粉吸入器可以利用各组成部分的自顶向下的装配来组装。 In certain embodiments, the dry powder inhaler can be assembled using top-down of the components assembled. 在一些实施例中,吸入器在尺寸上被设置为诸如从约I英寸到约5英寸之类的紧凑尺寸。 In some embodiments, the inhaler is arranged in size to a compact size such as from about I inch to about 5 inches and the like. 在某些实施例中,吸入器被设置为包括相对长方体、圆柱形、椭圆型、管形、方形、长方形和圆形的各种形状。 In certain embodiments, the inhaler is provided in various shapes including opposite cuboid, cylindrical, oval, tubular, square, rectangular and round.

[0096] 在本文所描述和例示的实施例中,吸入系统包括吸入器、药盒或容器以及干粉制齐U,吸入器配置有药盒,以通过利用允许诸如空气之类的气体进入吸入器的至少一个相对刚性的流动管道通路、有效地将干粉制剂流化、解聚或雾化。 [0096] Example embodiments described and illustrated herein, the inhalation system comprises an inhaler, a dry powder cartridge or container and made homogeneous U, the inhaler cartridge is arranged to allow through the use of a gas such as air into the inhaler at least one relatively rigid flow conduit pathway, effectively fluidizing the dry powder formulation, depolymerization or atomized. 例如,吸入器设置有用于进入和排出装有干粉的药盒的第一空气/气体通路,以及能够与排出药盒的第一空气流通路汇合的第二空气通路。 For example, the inhaler is provided for the first air into and out of the cartridge / powder with the gas passage, and a second air passage capable of converging the first air flow path is discharged kit. 例如,流动管道可以根据吸入器配置具有各种形状和尺寸。 For example, the flow conduit may have a variety of shapes and sizes according to the configuration inhaler. 例如,在美国专利申请12/484,125 (US 2009/0308390)、12/484,129 (US 2009/0308391)、12/484,137 (US 2009/0308392)和12/717,884 (US 2010/0197565)中公开了可以用在本吸入系统中的吸入器和药盒的示例,其中所有这些申请的关于吸入系统的所有公开内容全部通过引用结合于此。 For example, in U.S. Patent Application No. 12 / 484,125 (US 2009/0308390), 12 / 484,129 (US 2009/0308391), 12 / 484,137 (US 2009/0308392) and 12 / 717,884 (US 2010 / 0197565) discloses an example in the present inhalation system can be used in the inhaler and the cartridge, wherein all of the disclosures of all of these applications on the suction system are all incorporated herein by reference.

[0097] 在本文所例示的实施例中,各个吸入器可以使用适合的药盒。 [0097] In the embodiment illustrated herein, the inhaler may be used for each kit. 然而,当把吸入器和药盒设计为相互对应时,吸入系统可以更有效地工作。 However, when the cartridge and the inhaler is designed to correspond to each other, the intake system can work more efficiently. 例如,可以把吸入器的药盒安装区域设计为仅容纳特定的药盒,并且因此,例如作为安全参数帮助用户的关键区域或表面的、药盒和吸入器的开口的结构配置相互匹配或配合。 Structural configurations, for example, the opening, the inhaler can be designed to accommodate a cartridge mounting region only specific cartridge, and therefore, for example, as a critical security parameters to help the user area or surface of the cartridge and the inhaler match with each other or with . 本文中对应的吸入器和药盒的示例是,如吸入器302使用药盒170,吸入器900使用药盒150。 Examples herein correspond inhaler and cartridge is used as inhaler 302 cartridge 170, cartridge 900 uses the inhaler 150. 在美国专利申请12/484,125,12/484,129和12/484,137中公开了这些吸入器和药盒,其中所有这些专利申请的关于吸入器和药盒的所有公开、以及(如果适合)其他的或可替换的细节、特征和/或技术管景的教导,全部通过引用结合于此。 In U.S. Patent Application 12 / 484,125,12 / 484,129 and 12 / 484,137 discloses a cartridge and the inhaler, wherein the inhaler and cartridge on all disclosure of all these patent applications, as well as (if suitable) additional or alternative details, features and teachings / or techniques tube views, all incorporated herein by reference.

[0098] 在图1-9中例示了干粉吸入器的实施例。 [0098] In FIG 1-9 illustrates an embodiment of a dry powder inhaler. 在该实施例中,干粉吸入器具有两种配置,即,在图1-6和图9中所示的关闭配置和在图7和图8所示的打开配置。 In this embodiment, the dry powder inhaler has two configurations, i.e., in the closed configuration shown in FIGS. 1-6 and 9 and opening shown in FIG. 7 and FIG. 8 configuration. 在打开配置下的干粉吸入器302允许安装或拆除装有吸入药物的药盒。 Dry powder inhaler 302 in the open configuration to allow installation or removal of the cartridge with inhaled drug. 图1-6从各种视图描述了在关闭配置下的吸入器302,吸入器302具有包括壳体320,以及超出矩形体并且从矩形体向外延伸的嘴部330的相对矩形体。 Figures 1-6 describe the inhaler in a closed configuration from a variety of views 302, the inhaler 302 has a housing 320, and well beyond the mouth of the rectangular body portion extending outwardly from the rectangular body of relatively rectangular body 330. 嘴部330的一部分朝向用于接触用户的端部呈锥形,并且具有开口335。 A portion of the mouth portion 330 toward an end portion for contacting a user is tapered and has an opening 335. 吸入器302还包括齿轮机构363和滑板(sled)。 The inhaler means 302 further includes a gear 363 and the slide (sled). 吸入器302能够以自顶向下的装配方式、利用例如四个部分制成。 The inhaler 302 can be assembled in a top-down manner, for example using a portion made of four. 嘴部330还包括沿吸入器的纵轴线延伸的空气导管340,并且具有口腔放置部分312、空气入口310、空气出口335和药盒输出开口(cartridgeport opening) 355,其中空气出口335配置成使其表面相对于空气导管的纵轴成角度或成斜面,药盒输出开口355与壳体320和/或安装在壳体320中的药盒流体连通,以在使用时、使空气流从壳体或从安装在吸入器中的药盒进入空气导管340。 The mouth portion 330 also includes an air duct 340 along the longitudinal axis extending in the inhaler and having an oral placement portion 312, air inlet 310, air outlet 335 and the cartridge outlet opening (cartridgeport opening) 355, wherein the air outlet 335 is arranged so that angled surface with respect to the longitudinal axis of the air conduit or beveled kit output opening 355 in communication with the housing 320 and / or the fluid cartridge 320 mounted in the housing in order, in use, the air flow from the housing, or entering the air conduit 340 from cartridge installed in the inhaler. 图I在等距视图中图示了处于关闭位置的吸入器302,吸入器302具有比吸入器300更细长的体305,体305由壳体320和嘴部330的盖部308形成,其沿着壳体320延伸并且通过锁定机构312 (例如,突起)与壳体320配合。 Figure I illustrates an isometric view of the inhaler in the closed position 302, the inhaler 302 has a more slender body 300 than inhaler 305, 305 formed by the housing 320 and the cover portion 330 of the nozzle portion 308, which and extending along the housing 320 by a locking mechanism 312 (e.g., protrusions) 320 and the mating housing. 图2-6分别图示了图I的吸入器的侧视图、俯视图、底视图、远端和近端视图。 Figures 2-6 illustrate a side view of the inhaler I, a plan view, a bottom view, a distal end and a proximal end view. 如图所示,吸入器302包括嘴部330,嘴部330具有口腔放置部分312以及能够在至少已处连接到壳体320的、配置为盖308的延伸部分(如图7所示)。 As shown, the inhaler 302 comprises mouthpiece 330, mouthpiece oral placement section 330 having 312 and 320 can be connected to the housing is at least configured to cover the extension portion 308 (FIG. 7). 嘴部330可以通过铰链机构363在角方向上从距离用户的手的近端位置枢轴地打开。 Mouth from the proximal portion 330 may open pivotally from the position of the user's hand 363 by a hinge mechanism in an angular direction. 在该实施例中,吸入器302配置成还具有结合在铰链内的齿轮机构363(如图8所示),以打开吸入器或相对于壳体320打开嘴部330。 In this embodiment, inhaler 302 is configured also has a gear mechanism incorporated in the hinge 363 (FIG. 8), to open inhaler or the mouth opening 320 relative to the housing portion 330.

[0099] 齿轮机构或齿条319 (作为滑板317的一部分)和齿轮363作为铰链机构的一部分与嘴部一起配置,以与壳体320啮合,该壳体也可以配置成容纳滑板317。 [0099] or a rack gear mechanism 319 (as part of the slide plate 317) and the gear 363 as part of the mouth portion of the hinge mechanism arranged together to engagement with the housing 320, the housing may be configured to receive the slider 317. 在本实施例中,滑板317配置为单独的零件,并且具有配置成与配置在铰链机构上的大齿轮啮合的齿条的部分。 In the present embodiment, the slide plate 317 configured as separate parts, and has a rack arranged with the large gear arranged on the hinge mechanism engaging portion. 铰链机构363允许嘴部330在角方向上运动到吸入器302的打开配置或药盒卸载配置以及关闭配置或位置。 The hinge mechanism 363 allows the nozzle portion 330 is moved to the open configuration 302 of the inhaler or the cartridge unloading position or configuration and a closed configuration in an angular direction. 当吸入器通过嘴部330的运动而实现打开和关闭时,在吸入器300,302中的齿轮机构363可以驱使滑板以使滑板317在壳体320内同时运动,其中滑板317与作为齿轮机构363的一部分的齿条319—体地配置。 Is achieved when the inhaler is opened and closed, the gear mechanism 363 of the inhaler 300, 302 may be driven by the movement of the mouth portion 330 of the slide plate 317 to slide within the housing 320 while moving, the sliding plate 317 and 363 as a part of the gear mechanism a rack member arranged to 319-. 在与药盒一起使用时,吸入器的齿轮机构363可以在吸入器关闭期间通过滑板317的运动重新配置药盒,从药盒被安装在吸入器壳体或安装区域上之后的药盒保持配置(containment configuration)改变到当吸入器被关闭时的给药配置(dosing configuration)。 During the slide plate 317 when used with a cartridge, the inhaler gear mechanism 363 may be closed to reconfigure the motion inhaler cartridge, after being mounted on the inhaler housing or the cartridge from the cartridge mounting region holding configuration (containment configuration), when administered to change the configuration (dosing configuration) when the inhaler is closed. 嘴部330在利用药盒170的吸入后运动到打开吸入器配置或主题后的运动到可处理配置,已经实现了干粉制剂的加药。 The mouth portion 330 in the cartridge 170 by using suction to an open motion of the inhaler can be disposed or relating to the processing configuration has been achieved dosing dry powder formulation. 已经在本文所描述的实施例中,铰链和齿轮机构设置在吸入器的远端处,然而,可以设置其他的配置,以使得吸入器如蛘壳配置一样打开和关闭以加载或卸载药盒。 In embodiments have been described herein, the hinge and gear mechanism disposed at the distal end of the inhaler, however, other configurations may be provided, such as Yang inhaler housing arranged as to open and close the cartridge is loaded or unloaded.

[0100] 如图I所示并且在使用中,空气流通过空气入口310进入吸入器,并且通过空气入口355、同时进入经过药盒170的空气导管340。 [0100] As shown in FIG. I and, in use, air flow through the air inlet 310 enters the inhaler through the air inlet 355 and, at the same time into the cartridge 170 through the air duct 340. 在一个示例实施例中,嘴部330的从入口355到出口335延伸的空气导管340的内部体积大于约0. 2cm3。 In one exemplary embodiment, the nozzle 330 from the inlet 355 to the interior volume of the air duct outlet 335 is greater than about 340 extending 0. 2cm3. 在另一个示例实施例中,该内部体积约为0. 3cm3,或约为0. 4cm3,或约为0. 5cm3。 In another exemplary embodiment, the internal volume of about 0. 3cm3, or about 0. 4cm3, or about 0. 5cm3. 在又一个示例实施例中,嘴部的该内部体积大于约0. 2cm3。 In yet another exemplary embodiment, the internal volume of the nozzle portion is greater than about 0. 2cm3. 在示例实施例中,嘴部的内部体积的范围是从0. 2cm3到6. 5cm3。 In an exemplary embodiment, the range of the internal volume of the mouth portion is from 0. 2cm3 to 6. 5cm3. 装在药盒容器175内的粉末通过粉末容纳物的翻滚而流化或夹带到进入药盒的空气流中。 Contained within cartridge container 175 is fluidized or entrained powder entering the cartridge through tumbling of the powder contents of the air flow. 流化的粉末然后通过给药口(dispensing port) 173、127逐渐排出并且进入嘴部空气导管340,然后在排出出口335之前、被从空气入口310的空气流进一步解聚和稀释。 The fluidized powder then gradually discharged through the administration port (dispensing port) 173,127 and into the mouth of the air duct 340 and the outlet 335 prior to discharge, and is further depolymerized dilution air flow from the air inlet 310.

[0101] 在一个实施例中,壳体320包括一个或多个组成部分,例如,顶部316和底部318。 [0101] In one embodiment, the housing 320 includes one or more components, e.g., the top 316 and bottom 318. 顶部和底部以严密密封的方式彼此适应,形成容纳滑板317以及铰链和/或齿轮机构363的封装。 The top and bottom in a hermetically sealed manner adapted to each other, forming a package accommodating the slide plate 317 and a hinge and / or gear mechanism 363. 壳体320还配置成具有允许空气流进入壳体的内部的一个或多个开口309,用于在吸入器302的关闭位置处配合和紧固嘴部的盖部308的、诸如突起或卡环之类的锁定机构313。 Having a housing 320 is further configured to allow a flow of air into the interior of the housing or a plurality of openings 309 for fitting the lid portion and the closed position of the mouth portion of the fastening inhaler 302 308, such as protrusions or snap rings like the locking mechanism 313. 壳体320还配置成具有药盒保持器或药盒安装区域315,其配置成与吸入器所使用的药盒的类型相对应。 The housing 320 is further configured to have a cartridge holder or cartridge mounting area 315 which is configured to the type of inhaler used cartridge corresponds. 在该实施例中,药盒放置区域或保持器是在壳体320的顶部中的开口,其中药盒安装在吸入器302中以后、该开口还允许药盒的底部或容器落在滑板317上。 In this embodiment, the cartridge placement area or holder is an opening in the top of the housing 320 in which the cartridge 302 is mounted in the inhaler after the opening also allows the cartridge bottom portion or container 317 falls on the slide . 壳体还包括抓紧区域304、307,其配置成帮助吸入器的用户结实并牢固地抓住吸入器以将其打开,来加载或卸载药盒。 The housing further comprising gripping regions 304, 307, which is configured to assist a user of the inhaler strong and firmly grasp the inhaler to open it to load or unload the cartridge. 壳体320还包括配置成限定空气通路或导管的凸缘,例如两个平行凸缘303,其还配置成将空气流导入吸入器空气入口310,并且进入布置在吸入器中的药盒空气导管的药盒空气入口中。 Further comprising a housing 320 configured to define an air passageway or conduit flange, for example, two parallel flanges 303, which is further configured to intake air flow introduced into the air inlet 310, and into the air duct is arranged in the cartridge of the inhaler kit air inlet. 凸缘310还配置成防止用户挡住吸入器302的入口310。 Flange 310 is further configured to prevent a user from blocking the suction inlet 310 302.

[0102] 图7图示了图I的吸入器在打开配置下的等轴测试图,其中吸入器具有嘴部覆盖物,例如,帽342和药盒170,其中药盒170配置成与药盒安装区域相对应并且允许药盒安装在药盒保持器315中以供使用。 [0102] FIG 7 illustrates an isometric inhaler I tried in the open configuration and the like, wherein the suction nozzle portion having a cover, e.g., cap 342 and cartridge 170, wherein the cartridge 170 is configured with cartridge and allowing the mounting region corresponding to the cartridge mounted in the cartridge holder 315 for use. 在一个实施例中,在药盒被安装在药盒保持器315中以后,可以实现药盒从保持位置(如制造后所设置的)的重新配置,其中约盒保持器315配置在壳体320内,并且配置成适用于吸入器,以使得药盒在吸入器中具有适当的取向并且只能以一种方式或取向来插入或安装。 In one embodiment, after the holder is mounted in the cartridge 315 in the cartridge, the cartridge can be implemented to reconfigure from the holding position (as set after manufacture), and about which the cartridge holder 315 disposed in the housing 320 inside, and is configured to be adapted to the inhaler, such that the cartridge has the proper orientation in the inhaler and can only be inserted one way or orientation or mounting. 例如,药盒170可以配置有锁定机构310,其与配置在吸入器壳体中的锁定机构相配,例如,吸入器安装区域或保持器可以包括斜边310,斜边310会与要被安装在吸入器中的药盒(例如,药盒170)的斜边180对应。 For example, the kit 170 may be configured with a locking mechanism 310, which locking mechanism disposed in the inhaler housing mating, e.g., an inhaler holder or mounting area 310 may include a hypotenuse, the hypotenuse 310 can be mounted to the inhaler cartridge (e.g., cartridge 170) 180 corresponding to the hypotenuse. 在该实施例中,斜边形成了在滑板317的运动期间防止药盒从保持器315中弹出的锁定机构。 In this embodiment, the oblique side is formed to prevent the locking mechanism from the pop-up cartridge holder 315 during movement of the slide plate 317.

[0103] 在图8和图9所示的一个具体实施例中,药盒盖配置有斜边,以在使用时使其在壳体安装区域中保持牢固,该安装区域具有相配的斜边。 [0103] In a particular embodiment shown in FIGS. 8 and 9 embodiment, cover drugs hypotenuse arranged so that it remains firmly in the mounting region of the housing in use, the mounting area has a matching beveled edge. 图8和图9还示出了齿条机构319, 该齿条机构配置有滑板317以使得当吸入器302准备给用户服药时,药盒170的药盒容器175在药盒顶部的下方可滑动地移动,以在药盒顶部下表面的下方对齐容器,所述药盒顶部的下表面配置成在关闭的吸入器配置者药盒配药或给药位置或配置下具有给药口(一个或多个)。 Figures 8 and 9 also shows a rack mechanism 319, the rack mechanism 317 configured with sled 302 such that when the inhaler ready medication to a user, the cartridge 175 cartridge receptacle 170 at the top of the cartridge before sliding moved to the lower surface of the cartridge is aligned at the top of the container, the lower surface of the top of the cartridge configured to have the administration port in the closed configuration the inhaler cartridge by dispensing or dosing position or configuration (or a a). 由于药盒顶部相对于下表面突出,因此在给药配置中,通过药盒顶部的边缘和容器的边框形成空气入口。 Since the top surface of the cartridge with respect to the projection, and therefore dosing configuration, an air inlet is formed by the top edge of the frame and the container of the kit. 在该配置中,由空气入口、暴露到环境空气的药盒的内部体积以及在药盒顶部的开口或在药盒顶部中的给药口限定通过药盒的空气管道,该空气管道与嘴部的空气管道340流体地连通。 In this configuration, the air inlet is exposed to the interior volume of the cartridge ambient air and an opening at the top of the cartridge in the top cartridge or the administration port is defined by a cartridge air duct, the air duct and the mouth portion the air duct 340 communicates fluidly.

[0104] 吸入器302还可以包括嘴帽342以保护嘴部的口腔放置部分。 [0104] The inhaler may further include a nozzle 302 to the cap 342 protect the oral placement portion of the mouth portion. 图8描述了在打开配置下并且在药盒安装在药盒保持器中的条件下的图I的吸入器、在通过中间纵轴的横截面图,以及图9是在药盒配药或给药配置下的、在关闭状态下的图I的吸入器的通过中间纵轴的横截面图。 Figure 8 depicts in an open configuration and is mounted in a holding device of FIG I in the conditions in the cartridge in the inhaler cartridge, in cross-sectional view through the middle longitudinal axis, and in FIG. 9 is a kit or pharmaceutical administration configuration, the cross-sectional view through the central longitudinal axis of the inhaler in the closed state of FIG. I in.

[0105] 图8图示了安装在保持器或安装区域315中的药盒350的位置,并且示出了吸入器302和药盒170相对于彼此的内部组成部分,包括具有给药口327的凸起(boss) 326,齿轮机构360、363以及帮助设备保持在关闭配置的按扣380等。 [0105] FIG. 8 illustrates a position of the holder or mounted on the mounting region 315 of the cartridge 350, and shows the inhaler 302 and 170 to each other relative to the inner part of a kit, comprising the administration port 327 having a projection (boss) 326, and a gear mechanism 360,363 assist device remains in the closed configuration of snaps 380 and the like.

[0106] 图10-16图示了吸入系统的干粉吸入器的另一实施例。 [0106] Figures 10-16 illustrates another inhalation system of the embodiment of a dry powder inhaler. 图10描述了结构上与图 10 depicts the structure of FIG.

1-9所示的吸入器302类似地配置的、在打开配置下的吸入器900。 1-9302 inhaler shown similarly configured, in the open configuration the inhaler 900. 吸入器900包括嘴部930和壳体组件920,嘴部930和壳体组件920通过铰链相互连接,以使得嘴部930相对于壳体组件920枢轴地转动。 900,920 inhaler, the mouth portion 930 and the housing assembly includes a mouth portion 930 and the housing 920 via a hinge assembly connected to one another, so that the mouth portion 930 to rotate relative to the housing assembly 920 pivotally. 嘴部930还包括比壳体920宽的、一体形成的侧板932,侧板932与壳体突起905啮合以得到吸入器900的关闭配置。 Further comprising a nozzle portion 930 wider than housing 920, side plates 932 are integrally formed, plate 932 and housing engagement protrusion 905 to obtain a closed configuration the inhaler 900. 嘴部930还包括空气入口910、空气出口935 ;用于接触用户的唇部或嘴部的、从空气入口910延伸到空气出口935的空气流管道940,以及与吸入器的空气流管道940连同的、在底面上的孔955。 The mouth portion 930 also includes an air inlet 910, air outlet 935; for contacting the user's lip or mouth, extending from the air inlet 910 to air outlet 935 of the air flow duct 940 and an air suction duct 940 together with the flow , the hole 955 in the bottom surface. 图12图示了及入器900的分解图,其示出了包括嘴部930和壳体组件920的吸入器的组成部分。 And FIG. 12 illustrates an exploded view of the 900, which shows a part of the mouth portion 930 and includes a housing assembly 920 of the inhaler. 如图12所示,嘴部被配置成单个部件,并且还包括用于与壳体920铰接的、配置有913的棒、柱体或管911,以使得嘴部930相对于壳体920在角方向上移动来实现设备的关闭。 As illustrated, the mouth portion 12 is configured as a single member, and further comprising a housing and a hinge 920 disposed rods, cylinders or tubes 911,913 such that the mouth portion 930 at an angle 920 with respect to housing moves in the direction to achieve closure device. 空气通路912可以被设置到壳体,其可以向嘴部空气入口910引导空气流。 Air passage 912 may be provided to the housing 910 which can direct air flow to the nozzle portion of the air inlet. 空气通路912配置成使得,在使用中,放置在通路上的用户的手指不会限制或阻碍空气流进入空气管道940。 Air passage 912 is configured such that, in use, is placed in the path of the user's finger does not restrict or impede air flow into the air duct 940.

[0107] 图12图示了壳体920,其包括被制造为组成封装的两个部分,并且包括具有药盒放置或安装区域908和槽口918,其中槽口918配置成当吸入器在关闭配置下时,限定空气入口。 [0107] FIG. 12 illustrates a housing 920 which is fabricated as comprising a two-part package, and includes a cartridge placement or mounting area 908 and slots 918, where slots 918 configured such that when in the closed inhaler when configuration defining an air inlet. 图12图示了作为封装的壳体920,其还包括便于制造的两个部分,但可以使用更少或更多的部分。 12 illustrates housing 920 as a package, which facilitates further comprising two portions made, but fewer or more parts. 外壳成型的底部没有开口并且包括托盘922,并且底部与顶部或盖部925连接以形成封装或壳体920。 No openings shaped housing bottom and includes a tray 922, and the bottom and top or cover portion 925 are connected to form a package or housing 920. 托盘922配置有槽口914,槽口914配置在托盘922的容纳与嘴部930形成铰接的棒、柱体或管911的远端。 Tray 922 is configured with notches 914, 914 disposed in slot 922 of the tray 930 accommodating the mouth portion form a hinge rod, cylinder or tube 911 in the distal end. 托盘922还容纳滑板917。 Tray 922 also accommodates the slide 917. 滑板917配置成在托盘922内可移动,并且具有药盒容纳区域921和具有与嘴部930的齿或齿轮相配合的开口915的臂状结构,以使得在关闭设备以使用时,嘴部930相对于壳体920的运动使滑板在近端方向上移动,导致滑板紧挨着位于吸入器保持器或安装区域908中的药盒容器,并且能够将容器从保持位置改变到给药位置。 The slider 917 is configured to be movable within tray 922 and has a cartridge receiving area 921 and the opening 915 of the arm structure or gear teeth 930 of the nozzle portion having a cooperating, such that when the closing device to use, the mouth portion 930 movement relative to the housing of the slide plate 920 is moved in the proximal direction causes the slider is located next to the suction holder or cartridge mounting area 908 of the container, and the container can be changed from the holding position to the administering position. 在该实施例中,位于药盒保持器908中的药盒具有在给药配置下、面向吸入器或用户的近端的空气进入开口。 In this embodiment, the cartridge located in the cartridge holder 908 having a configuration in administration, inhaler or proximal end of the air inlet opening facing the user. 壳体盖部925配置成,使其能够通过具有,例如,作为紧固机构的、从底部边缘延伸的突起926而牢固地连接到托盘922。 The housing cover 925 is configured so that it can have by, for example, as a fastening mechanism, and the protrusion 926 fixedly connected to the tray 922 extending from the bottom edge. 图12图示了在打开配置下的吸入器900,其描述了被安装在吸入器的安装区域中的、 在保持配置中的药盒150的位置和取向。 12 illustrates inhaler 900 in the open configuration, which describes the position and orientation of the cartridge in the holding arrangement 150 is mounted in the mounting area of ​​the inhaler. 图13进一步图示了在打开配置下的吸入器900,其中吸入器900具有在保持配置下的位于药盒保持器中的药盒150。 Figure 13 further illustrates inhaler 900 in the open configuration, wherein the inhaler 900 has positioned the cartridge holder holding the cartridge 150 configuration. 图14图示了在图13中的吸入器的中间纵轴截面图,其示出了在药盒容器151的保持配置下、齿轮913相对于滑板917的位置,其中药盒容器151紧挨着滑板917。 14 illustrates a central longitudinal sectional view of the inhaler in FIG. 13, showing a cartridge in the holding vessel configuration 151, the gear 913 with respect to the slide plate 917, wherein the kit container 151 immediately 917 skateboarding. 在该实施例中,容器151相对于药盒顶部156移动。 In this embodiment, the container 151 relative to the top cartridge 156 moves. 在关闭吸入器900 (图15)时并且随着吸入器900移动到实现关闭配置,滑板917推动容器151直到实现给药配置,并且嘴部的孔955在药盒凸台(boss) 126上滑动,以使得给药口127与嘴部管道940连通并且通过空气进入孔918、药盒空气出口919和在空气管道940中的给药口127建立空气流通路。 When closing inhaler 900 (FIG. 15) with movement of the inhaler and 900 to implement the closed configuration, the slider 917 push the container 151 until a dosing configuration, and the nozzle hole portion 955 slides on the cartridge boss (boss) 126 , so that the administration port 127 communicates with the pipe mouth portion 940 and through the air inlet aperture 918, cartridge air outlet 919 and administration port 127 of the air duct 940 to establish an air flow path. 从图16可知,嘴部930以及空气流管道940在大约中间到远端具有较为锥形的、沙漏形状的配置。 Seen from FIG. 16, nozzle section 930 and an air flow conduit 940 to the distal end with a more tapered, arranged approximately in the middle of the hourglass shape. 在该实施例中,滑板917配置成使得,当在使用后打开吸入器时,滑板不能将药盒重新配置为保持配置。 In this embodiment, the sliding plate 917 is configured such that, when the inhaler is open after use, the sled can not reconfigure cartridge holding configuration. 在本实施例的一些变体中,根据所使用的粉末药物可以或期望重新配置药盒。 Some variants of the embodiments in the present embodiment, the powdered drug used in accordance with the kit can be reconfigured or desired.

[0108] 在本文所公开的实施例中,吸入器孔(例如355、955)可以设置有密封部分,例如,挤压肋(crushed ribs)、密封表面、垫圈和O型圈等,以防止空气泄露到系统中,使空气流仅在药盒中穿行。 [0108] In embodiments of the herein disclosed embodiment, the suction holes (e.g., 355,955) may be provided with a sealing portion, e.g., crush ribs (crushed ribs), a sealing surface, and an O-ring gasket to prevent air leak into the system, air flow only walk through in the kit. 在其他实施例中,为了实现密封,可以将密封部分设置到药盒。 In other embodiments, for sealing, the sealing portion may be provided to the kit. 吸入器还可以设置有一个或多个解聚区,其配置来尽量减少粉末的集结或沉积。 The inhaler can also be provided with one or more depolymerization zone configured to minimize powder buildup or deposition. 解聚区设置在例如药盒中,包括在容器和给药口中,并且设置在嘴部的空气管道中的一个或多个位置处。 Depolymerization zone is provided at one or more positions, for example in a kit, comprising a container and administration in the mouth, and disposed in the air duct in the mouth.

[0109] 上面描述了诸如分别在图10、13、14、16-21以及图7-9,22-30中图示的药盒150、170之类的、与吸入器一起使用的药盒实施例。 [0109] In the above-described embodiment, such a kit for use with the FIG 10,13,14,16-21 and illustrated in FIG. 7-9,22-30 kit 150,170 and the like, each inhaler example. 本发明的药盒配置为形成具有至少两种配置的封装,并且在存储的、紧密封或被包含的位置中装有干粉药物。 The kit of the present invention is configured to form a package having at least two configurations, and with the dry powder medicament in a storage, tightly sealed or contained position in. 在该实施例和其他的实施例中,药盒可以在吸入器中从粉末保持位置重新配置到吸入或给药配置。 In the embodiment and other embodiments of the embodiment, the kit may be reconfigured to be administered by inhalation or arranged in a holding position from a powder inhaler.

[0110] 在某些实施例中,药盒包括盖或顶部和具有一个或多个孔的容器,包括保持配置和给药配置,包括外表面、限定内部体积的内表面;并且保持配置限制到内部体积的连通,并且给药配置形成通过内部体积的通路、以允许空气流以预定方式进入并且排出内部体积。 [0110] In certain embodiments, the kit comprises a container having a lid or top and one or more holes, comprising administering to maintain configuration and configuration, comprising an outer surface, an inner surface defining an internal volume; and remains limited to the configuration communication with the interior volume, and is administered through the internal volume of the disposed passage formed to allow air to flow into and discharges internal volume in a predetermined manner. 例如,药盒容器可以配置成使得,进入药盒空气入口的空气流在内部体积中被引导穿过空气出口、以计量离开药盒的药物从而控制粉末的排出速率;并且其中在药盒中的空气流能够在通过给药孔排出之前、在内部体积中、在与空气排出流方向基本垂直的方向上翻腾、混合和流化粉末。 For example, the kit containers may be configured such that the air entering the cartridge air inlet flow is directed through the air outlet in the interior volume, leaving the drug metering cartridge to control the rate of discharge of the powder; and wherein in the kit of air flow can be in the interior volume, in the flow direction of the air discharge direction substantially perpendicular to churn prior to discharge through the delivery opening, and the fluidized powder mix.

[0111] 在一个实施例中,药盒可以用一个或多个指示物编码,指示物包括标签、蚀刻图案、颜色、装饰玻璃粉、凸缘和皱纹等。 [0111] In one embodiment, the kit may be one or more coded indicator, the indicator comprises a label, an etching pattern, color, decorative glass frit, and the flange wrinkles. 例如,如果选择了颜色,那么可在药盒的制造期间结合与塑料和药物制剂相容的或者药学上可接受的各种类型的颜料。 For example, if a color is selected, it may be combined with the plastic and compatible pharmaceutical formulation or a pharmaceutically acceptable types of pigments during the manufacture of the kit. 在该实施例和其他实施例中,颜色可以表示特定的活性成分或剂量强度,例如,一个绿色的盖子可以指示6个单位的6红色、紫色、黄色、橙色等。 In this embodiment and other embodiments, the color may represent a particular dosage strength active ingredient or, for example, may indicate a green lid 6 of 6 units of red, purple, yellow, orange and the like.

[0112] 图17进一步图示了包括顶部或盖156和限定内部空间或体积的容器151。 [0112] FIG. 17 illustrates a further container 151 includes a top or lid 156 and defining an interior space or volume. 图18进一步例示了药盒顶部15,其具有两端,并且包括在纵轴X的两端处的凹陷区域154和凸台126,以及在纵轴X方向上沿着侧边的相对矩形板组152,板152在它们的两端一体地配置并连接到顶部156。 Figure 18 further illustrates the top cartridge 15, which has two ends, and including 126, and a rectangular plate group along opposite recessed area 154 at both ends of the longitudinal axis X and the boss side in the longitudinal direction X 152, plate 152 is integrally configured and connected to the top 156 at their ends. 药盒顶部156的边缘158从顶部156的沿纵轴X方向的侧边向下延伸,并且通过纵向空间或狭长口157与凸台区域126和凹陷区域154分开。 The top edge 156 of the cartridge 158 extends downwardly from the side edges along the longitudinal direction X of the top 156, and separated by a space or longitudinal opening 157 and elongated projections 126 and the recessed area 154 region. 图17-21还示出了每个板152还包括凸缘153,凸缘153结构上配置成与容器151的突起或翼166配合, 支撑容器151,并且允许容器151从凹陷区域154下的保持位置移动到凸台区域126下的给药位置。 17-21 also shows that each panel 152 further includes a flange 153, 153 arranged on the flange structure 166 to cooperate with the container projections or wings 151, 151 supporting the container and allowing the container 151 held at the recessed region 154 from position to the administering position in the projection region 126. 板152在每个端部结构上配置有止动器132,以防止容器151移动越过它们连接到边缘158的端部。 Plate 152 is disposed on each end portion of the stopper structure 132 to prevent the container 151 is moved over the end edges thereof are connected to the 158. 在该实施例中,容器151或盖156可以例如通过在顶部156上平移运动而可移动,或者顶部156相对于容器151可移动。 In this embodiment, container 151 or lid 156 can for example be moved by translational movement on the top 156, or top 156 is movable relative to the container 151. 在一个实施例中,根据吸入器的配置,当盖或顶部156固定时,容器151通过在位于盖156上的凸缘153上滑动而可移动,或者盖156通过在固定的容器151上滑动而可移动。 In one embodiment, the inhaler according to the configuration, when the lid or top 156 is fixed, the container 151 slidably movable on the flange 153 on the cap 156 by sliding the cover 156 or on a stationary container 151 it can move. 在凸台126附近的边缘158具有凹入区域,该凹入区域在药盒的给药配置下形成入口119的边缘的一部分。 Around the edges boss 126,158 has a recessed region, a portion of the edge of the inlet of the recessed area 119 is formed in the dosing configuration of the cartridge.

[0113] 图19图示了药盒150的底视图,其示出了诸如容器151、给药口127、板152、凸缘153以及较空或凹入的、在凸台126下方的区域或底面168等结构在保持配置下的关系。 [0113] FIG. 19 illustrates a bottom view of cartridge 150 showing container 151 such as the administration port 127, plate 152, the flange 153 and the relatively empty or concave in the region 126 below the boss or holding the bottom surface 168 and other structures in relation configuration. 图20图示了通过在保持配置下的药盒150的中间纵轴X的截面,其示出了在凹入区域154处与盖156紧密接触并且由凸缘153支撑的容器151。 20 illustrates a cross-section through the middle of the lower holder disposed longitudinal axis X of the cartridge 150, which is shown in the recess 154 and the lid 156 into close contact with the container 151 supported by the flange 153. 凸台126的下侧是空的并且可以看出其处于比容器151的上边缘相对较高的位置处。 The lower side of the boss 126 is hollow and can be seen which is at a relatively higher than the upper edge of the container 151 position. 图21图示了在给药配置下的药盒150,其中容器151的上边缘和凸台126区域下方的板158形成允许空气流进入药盒的内部151的人口119。 Figure 21 illustrates a cartridge 150 in the dosing configuration, wherein the upper edge of the bottom plate 151 of the container 126 and the boss region 158 is formed to allow air to flow into the interior 119 of the kit 151 of population.

[0114] 在另一个实施例中,在图22-30中图示了平移的药盒170,药盒170是药盒150的替代实施例并且可与,例如图1-9所示的吸入器302 —起使用。 [0114] In another embodiment, cartridge 170 is illustrated in FIG translating 22-30, cartridge 170 is a cartridge 150 in alternative embodiments and may be, for example, the inhaler shown in FIG 1-9 302-- used together. 图22描述了药盒170,其包括具有顶部或盖172和限定内部空间的容器175的封装,其中该药盒以保持配置示出。 Figure 22 depicts a kit 170, comprising a package having a top or lid 172 and container 175 defining an interior space, wherein the cartridge holder to the configuration shown. 在该药盒配置中,药盒顶部172配置成与容器容器175形成密封结构,并且容器或盖相对于彼此可移动。 In this cartridge configuration, the cartridge top 172 of the container 175 is configured to form a seal with the container structure, and the container or lid is movable relative to one another. 药盒170可以从保持位置(图22和图29)配置到给药位置(图24-28,图30),并且可以配置到例如在药盒的中间处的可弃置位置(未示出)以指示药盒已被使用。 The kit 170 may be configured from the holding position (FIGS. 22 and 29) to a dosing position (FIGS. 24-28, FIG. 30), for example, and may be configured to be disposed at the position of the intermediate cartridge (not shown) to indicating kit has been used. 图22还图示了药盒170的各种特征,其中顶部172包括侧板171,侧板171配置成部分地覆盖容器的外部。 FIG 22 also illustrates the various features of cartridge 170, wherein top 172 comprises side panel 171, side panels 171 configured to partially cover the outside of the container. 每个侧板172包括在其下边缘处的凸缘177,凸缘177形成支撑容器175的翼状结构的轨道,允许容器175沿着顶部172的下边缘移动。 Each side plate 172 includes a flange 177 at the lower edge thereof, the wing-like flanges 177 forming the track support structure 175 of the container, allowing the container 175 moves along the lower edge of the top 172. 药盒顶部172还包括在一端处的外部的相对平坦的表面、具有开口或给药口173的相对矩形的凸台174以及内部配置成以紧密封的方式保持容器175的容纳物。 The kit further includes a top 172 relatively flat surface at the outer end of the boss 174 and the internal mode is configured to be administered tightly sealed opening or mouth 173 having a relatively rectangular holding container 175 the contents. 在一个实施例中,给药口可配置成具有各种尺寸,例如,开口的宽度和长度可以是,在给药口的位于药盒内部的入口处,宽度是从约O. 025cm到约O. 25cm并且长度是从约O. 125cm到约O. 65cm。 In one embodiment, oral administration may be configured to have various sizes, for example, the width and length of the opening may be, in the cartridge located inside the entrance opening of administration, the width is from about O to about O. 025cm . 25cm and a length of from about O. 125cm to about O. 65cm. 在一个实施例中,给药口入口测量后有约O. 06cm的宽、约O. 3cm的长。 In one embodiment, the inlet port after administration measuring approximately 06cm wide of O., O. about 3cm in length. 在某些实施例中,药盒顶部172可以包括各种形状,这些形状可以包括用于将药盒定位在正确的方位上以适当地安装在保持器中的抓紧表面(例如耳片176、179)和其他配置,以及可靠地适用于对应的吸入器的例如倒角边或斜边180等的紧固机构。 In certain embodiments, the top of the kit 172 may include various shapes which may include a cartridge positioned in the correct orientation to gripping surfaces appropriately mounted in the holder (e.g., tabs 176,179 ) and other configuration, for example, bevelled edges and oblique or 180 is reliably applied to the corresponding inhalers like fastening means. 凸缘、凸台的外部几何形状、耳片和各种其他形状可以构成关键表面(keyingsurface),该关键表面能够指示、帮助和/或迫使吸入器中的药盒的适当的布置。 Flanges, external geometry of the boss, tabs, and various other shapes can constitute a critical surface (keyingsurface), which can indicate the key surface, help and / or force suitable arrangement of the inhaler cartridge. 此外,为了将由药盒提供的特定的药物或配药与特定的吸入器相关联,这些结构可以从一个吸入器-药盒对系统改变到另一个。 In addition, for a specific drug or dispensing with a particular inhaler associated cartridge will be provided, these structures may vary from one inhaler - cartridge system changes to another. 以这种方式,可以防止用于与第一药物或配药相关联的吸入器的药盒被放置到或被用于与第二药物或配药相关联的相似的吸入器中。 In this manner, it is possible to prevent the drugs for being placed in the first or dispenser associated to the inhaler or cartridge for dispensing a second medication or similar inhaler associated.

[0115] 图23是例示了具有凸台174、给药口173、凹入区域178以及耳片176和179的药盒顶部172的总体形状的俯视图。 [0115] FIG. 23 is a diagram illustrating a boss 174 having a dosing port 173, the recessed area 178 and a plan view of the overall shape of the tab 176 and the top 179 of the cartridge 172. 图24是药盒170的底视图,其示出了在给药位置的容器175通过其翼状突起182被顶部172的各个凸缘177支撑。 FIG 24 is a bottom view of cartridge 170, which shows the position of the container 175 through the administration of wing-like projections 182 which support the respective flanges 177 of the top 172. 图25描述了在给药配置下的药盒170,药盒170还包括由在药盒顶部172上的槽口和容器175的上边缘形成的空气入口181。 Figure 25 depicts an air inlet 181 formed by the upper edge of the container and the notches 172 on the top of the cartridge 175 in the dosing configuration of the cartridge 170, the cartridge 170 further comprises a. 在该配置中,空气入口181与药盒的内部连通,并且与给药口173 —起形成空气管道。 In this configuration, the air inlet 181 communicates with the interior of the cartridge, and the administration port 173-- formed from air duct. 使用时,药盒空气入口181配置成引导在给药口172处的进入药盒内部的空气。 In use, the cartridge air inlet 181 configured to direct air into the interior of the opening 172 of the cartridge administration. 图26 从给药配置的另一端或图25的后视图描述了药盒170。 The other end of FIG. 26 from the administration or the configuration of FIG. 25 is a rear view of the cartridge 170 is described.

[0116] 图27图示了药盒170的侧视图,其示出了诸如容器175、凸台174、侧板172和耳片176等的结构在给药配置下的关系。 [0116] FIG. 27 illustrates a side view of the cartridge 170, which shows such a container 175, the structure of the boss 174, side plates 172 and the tabs 176 or the like in relation dosing configuration. 图28图示了用于使用的在给药配置下的包括容器175和顶部172的药盒170,其中顶部172具有相对矩形空气入口181和贯穿凸台174的相对矩形给药口173,凸台174相对中间地位于药盒顶部172的上表面上。 28 illustrates a configuration for use in the administration of the cartridge 170 includes a container 175 and a top 172, which top 172 having a relatively rectangular air inlet 181 and through the boss 174 relative to the rectangular opening 173 of the administration, the boss 174 located on the opposite upper surface of the middle of the top 172 of the cartridge. 凸台174配置成装配到在吸入器嘴部的壁中的孔中。 Bosses 174 configured to fit into a hole in the wall of the mouth portion of the inhaler in. 图29和图30分别图示了在保持配置和给药配置下、通过药盒170的中间轴线X的截面图,其示出了容器175在凹入区域178的底面处与盖172接触并且由凸缘177支撑,凸缘177形成用于容器从一个位置滑动到另一位置的轨道。 Figures 29 and 30 illustrate a configuration and administration of the holding configuration, cross-sectional view through the center axis X of the cartridge 170, which shows the container 175 in the recess in contact with the bottom surface 178 and a cover 172 a support flange 177, the flange 177 forming the track for the container to slide from one position to another position. 如图29所示,在保持配置下,容器175在凹入区域178处与药盒顶部172的底面形成密封。 29, in the retention configuration, the container 175 forms a seal with the bottom surface of the top of the cartridge 172 at the recessed area 178. 图30描述了在给药配置下的药盒170,其中容器在凹入区域178的相对端,并且容器175和药盒顶部形成空气入口181,空气入口181允许环境空气进入药盒170,并且与给药口173和容器175的内部一起形成空气管道。 30 depicts a kit at 170 dosing configuration, wherein the recessed area in the opposing end of the container 178 and the container 175 is formed the air inlet 181 and cartridge top air inlet 181 allows ambient air to enter cartridge 170, and with together form an air duct for internal administration port 173 and the container 175. 在该实施例中,药盒顶部的实现给药位置的底面是相对平坦的并且容器175的内表面配置成一定程度上的U形。 In this embodiment, the bottom surface of the top of the site of administration to achieve a kit is relatively flat and the inner surface of the container 175 is disposed on a U-shape to some extent. 凸台174配置成轻微地突出于药盒顶部172的上表面。 Boss 174 is configured to slightly protrude to the surface of the top 172 of the cartridge.

[0117] 在药盒的其他实施例中,药盒适用于适合使用可转动机构的干粉吸入器,其中可转动机构用于将吸入器或药盒从保持配置移动到给药位置(其中药盒顶部相对于容器可移动),或者用于在将给药口与容器对齐时相对于顶部移动容器以移动到给药位置,或者移动容器或顶部以移动到保持配置。 [0117] In other embodiments of the kit, the kit is suitable for use for dry powder inhaler rotatable means, wherein the turning mechanism for an inhaler or cartridge configured to move from the holding position is administered (cartridge wherein top movable relative to the container), or for the administration port when the container is aligned relative to the top and moving the container to move to the site of administration, or moving the container or the top to move to the holding configuration.

[0118] 在本文所述的实施例中,根据所使用的干粉制剂,药盒可以被配置成以各种量输送单个单位、预计量剂量的干粉药物。 [0118] In the embodiments described herein, the dry powder formulation is used, the kit may be configured in various amounts conveying a single unit, pre-metered dose of dry powder medicament. 诸如药盒150、药盒170之类的药盒可以结构上配置成容纳一剂(例如从O. Img到约50mg)的干粉制剂。 , Such as kit 150, like the kit 170 may be configured to receive a cartridge (e.g. from O. Img to about 50mg) dry powder formulation structure. 因此,容器的尺寸和形状可以根据吸入器的尺寸和要输送的粉末药物的量或团而变化。 Thus, the size and shape of the container may vary depending on the size and the amount of powdered medicament to be delivered inhaler or group. 例如,容器可以是具有相对平整的两个侧面并且两侧面之间具有从约O. 4cm到约2. Ocm的近似距离的相对圆柱形状。 For example, the container may have two opposing sides relatively flat and has a cylindrical shape approximate distance from about O. 4cm to approximately 2. Ocm between the side surfaces. 为了优化吸入器性能,药盒内侧沿Y轴的高度可以根据想要装在腔内的粉末的量来改变。 To optimize the inhaler performance, the inside of the cartridge along the Y axis according to the desired height may be installed in the amount of the powder within the cavity is changed. 例如,5mg到15mg的粉末填充最适合需要约O. 6cm到约I. 2cm的高度。 For example, 5mg to 15mg of powder is filled for the most require about O. I. 2cm height of about 6cm.

[0119] 在实施例中,提供了用于干粉吸入器的药物药盒,其包括:配置成保持药物的封装;允许空气进入所述封装的至少一个入口;以及允许流出所述封装的至少一个给药口;所述至少一个给药口配置成引导响应于压力差、在所述封装内的所述至少一个给药口处进入所述至少一个入口的气流。 [0119] In an embodiment, there is provided a pharmaceutical kit for the dry powder inhaler, comprising: a package configured to hold a medicament; allows air to enter the package at least one inlet; and allowing at least a flow out of the package oral administration; administering said at least one port configured to direct response to a pressure difference, in said at least one administration of the package opening at least one gas flow into said inlet. 在一个实施例中,所述吸入器药盒由高密度聚乙烯塑料形成。 In one embodiment, the inhaler cartridge is formed from high density polyethylene plastic. 所述药盒具有容器,其中该容器具有限定内部体积的内表面并包括彼此相邻的底部和侧壁,并且具有一个或多个开口。 The kit has a container, wherein the container has an inner surface defining an internal volume and comprising a bottom and side walls adjacent to each other, and having one or more openings. 所述药盒具有杯状结构并且具有带有边缘的一个开口,并且其由可配置成限定一个或多个入口以及一个或多个给药口的药盒顶部和容器底部构成。 The kit having a cup-shaped configuration and having an opening with an edge, and which may be configured to define the one or more inlets and one or more of the top and bottom of the container administration port configuration kits. 药盒顶部和容器底部可配置成保持位置以及配药或给药位置。 The top and bottom of the container cartridge may be configured to maintain the position and the dispensing or dosing position.

[0120] 在本文所述的实施例中,干粉吸入器和药盒形成吸入系统,由于该系统可以通过改变其气流管道在任何部分的横截面积来实现,因此该系统在结构上可配置成,实现可调的或模块化的气流阻力。 [0120] In the embodiments described herein, dry powder inhaler and cartridge form an inhalation system, since the system can be implemented by changing the cross-sectional area of ​​any portion of its air flow duct, so that the system may be configured in structure implement an adjustable or modular airflow resistance. 在一个实施例中,干粉吸入器系统可以具有从约O. 065到约O. 200 ( V kPa)/I每分钟的气流阻力值。 In one embodiment, the dry powder inhaler system can have from about to about O. 065 O. (V kPa) / I value of the airflow resistance of 200 per minute. 在其他实施例中,可以采用止回阀,以在达到诸如4kPa等的期望的压降(在这一点处,期望的阻力达到本文所给出的范围内的值)之前防止气流通过吸入器。 In other embodiments, the check valve may be employed to achieve the desired pressure drop, such as 4kPa or the like (at this point, the desired resistance reaches a value within the range given herein) prevents the airflow through the inhaler before.

[0121] 在本文所述的实施例中,干粉吸入器配置成在使用中具有预定的流量比例分配,使第一气流通路通过药盒并且使第二气流通路通过例如嘴部空气管道。 [0121] In the embodiments described herein, dry powder inhaler configured to have a predetermined flow rate ratio distribution, in use, the first cartridge and the flow path through the second flow path through the air duct such as the mouth portion. 图31和图32描述了由引导流量分配比例的药盒和吸入器的结构配置所建立的空气管道的示意图。 31 and FIG. 32 depicts a schematic configuration of the guide structure of the flow distribution ratio of the inhaler and cartridge established air duct. 图32图示了干粉吸入器的实施例的气流的运动,该干粉吸入器的实施例示出了在给药位置中的吸入器的气流通道(如箭头所示)。 FIG 32 illustrates an embodiment of moving gas stream of the dry powder inhaler, the dry powder inhaler in Example illustrates the air flow passage the inhaler in the dosing position (as shown by arrow).

[0122] 在吸入器内的质量流的部分约是整个药盒流动通路的体积的20%至70%,并且约30%至90%通过嘴部管道的开始部分。 [0122] section in the inhaler mass flow volume is about 20-70% of the whole cartridge the flow path, and from about 30 to 90% by the beginning of the mouth portion of the duct. 在该实施例中,通过药盒的气流分配以翻腾的方式混合药物,以流化或雾化在药盒容器中的干粉药物。 In this embodiment, in a somersault manner by mixing the drug dispensing cartridge stream of atomized or fluidized dry powder medicament in the cartridge container. 在容器内的流化粉末的气流然后使粉末上升,并且逐渐使粉末颗粒通过给药口排出药盒容器,然后进入嘴部管道的剪切空气流与从药盒容器排出的含有药物的空气流汇合。 Stream of fluidized powder in the container the powder is then increased, and gradually the powder particles discharged by administration of the kit container mouth, and the mouth of the conduit into the air flow and the air shear drug-containing stream discharged from the container cartridge convergence. 来自药盒的预计量或计量的排出气流与进入嘴部的空气管道的旁路气流汇合,以在排出嘴部出口并进入患者之前进一步稀释并解聚粉末药物。 The kit is expected from the intake air duct and the exhaust stream of the mouth portion of the bypass airflow metered amount or confluence of the discharge nozzle to the outlet portion and further diluted before the patient enters and deagglomerated powdered medicament.

[0123] 在又一实施例中,提供了用于向患者输送干粉制剂的吸入系统,其包括吸入器,该吸入器包括配置成容纳容器的容器安装区域,以及具有至少两个进气孔和至少一个出气孔的嘴部;其中所述至少两个进气孔中的一个进气孔与容器区域流体地连通,并且所述至少两个进气孔中的一个经由配置成绕过容器区域的流动路径与所述至少一个出气孔流体地连通,以向患者输送干粉药物;其中配置成绕过容器区域的流动管道在吸入期间通过吸入器的总流量的30%至90%。 [0123] In yet another embodiment, there is provided an inhalation system for delivering a dry powder formulation to a patient, comprising an inhaler, the inhaler comprising a container mounting area configured to receive the container, and having at least two inlet holes and the at least one exit hole of the nozzle portion; wherein the at least one inlet opening two intake port fluidly communicating with the container area, and wherein the at least two inlet hole in a region via a bypass arranged in the container at least one flow path and said air outlet in fluid communication to deliver dry powder medicament to a patient; wherein the flow conduit configured to bypass the container area during inhalation by 30-90% of the total flow of the inhaler.

[0124] 在另一个实施例中,也提供了用于向患者输送干粉制剂的吸入系统,其包括干粉吸入器,该干粉吸入器包括容器区和容器;组合的干粉吸入器和容器被配置成在给药配置下具有刚性流动管道,以及提供使用时用于吸入系统的粉末解聚的机构的多个结构区;其中用于解聚的多个机构中的一个是具有在O. 25mm和3_之间的最小尺寸的、在容器区中的结块尺寸排除孔。 [0124] In another embodiment, the inhalation system is also provided for delivering a dry powder formulation to a patient, comprising a dry powder inhaler, the dry powder inhaler comprising a container region and a container; a combination of a dry powder inhaler and container is configured having a rigid flow conduits, and a plurality of structural regions powder inhalation system for providing a mechanism using depolymerized under dosing configuration; wherein a plurality of means for having a depolymerized and in O. 25mm 3 _ between the minimum size, agglomerate size exclusion aperture in the container region. 刚性流动管道指的是在重复使用后几何形状不变的吸入系统的空气管道,即,管道保持相同或恒定并且不随着使用而变化,这与利用胶囊和泡罩的穿刺机制来工作的系统相反,这种系统的管道配置随着胶囊不同或泡罩不同而出现变化。 Refers to a rigid flow conduit after repeated use of the same geometric shape of the intake air duct system, i.e., the pipe remain the same or constant and does not change with use, which is opposite to the system using the capsule and the blister piercing mechanism to work , such a pipeline system configuration vary from different blister or capsule occurs.

[0125] 在替换实施例中,提供了用于向患者输送干粉制剂的吸入系统,其包括容器和包括嘴部的干粉吸入器;组合的干粉吸入器和容器被配置成在给药配置中具有刚性流动管道、以及在使用时提供用于吸入系统的粉末解聚机构的多个结构区域;其中所述多个解聚机构中的至少一者是,配置在嘴部的空气管道引导在与容器流体连通地排出孔处的流体。 [0125] In an alternative embodiment, a dry powder inhalation system for delivering the formulation to a patient, comprising a container and a dry powder inhaler includes a nozzle portion; a combination of a dry powder inhaler and container is configured to have a configuration administration rigid flow conduits, and a plurality of structural regions powder depolymerization mechanism is provided for use in a suction system; wherein said plurality of depolymerization at least one mechanism is disposed in the air duct is guided in the mouth portion of the container fluid outlet in fluid communication with the orifice. 在特定的实施例中,吸入系统包括容器,该容器还包括杯状结构的粘性粉末解聚机构,该杯状结构配置成引导进入容器的气流在杯状结构的内部体积中旋转、再流通并使粉末药物上升以带走在流体中的粉末块,直到粉末团在排出容器之前足够小。 In a particular embodiment, the inhalation system comprises a container structure further comprises a cup-shaped cohesive powders depolymerization mechanism, the cup-shaped structure is configured to rotate within the volume of the cup-shaped structure to guide the airflow into the vessel, and recirculation rise to entrain powdered medicament powder in the fluid block until the powder mass prior to discharge of the container sufficiently small. 在该实施例中,杯状结构具有配置成防止气流停滞的一个或多个半径。 In this embodiment, the cup-like structure configured to prevent having a stagnant airflow or more radii. ·[0126] 这里所述的实施例中,药盒在结构上配置成在水平轴和竖直轴上靠近给药口处具有进入开口。 * [0126] Example embodiments described herein, the cartridge is structurally configured having the inlet opening near the level of administration and on the vertical axis of the shaft opening. 例如,入口到给药口的接近程度可以是在大约一个药盒宽度上紧邻空气入口,但这种关系可以根据流速、粉末的物理和化学性质而变化。 For example, the inlet port to the proximity of administration may be close to the air inlet on the cartridge about a width, but this relationship may vary depending on the flow rate, physical and chemical properties of the powder. 由于这种接近程度,来自入口的气流越过开口到达在药盒内的给药口从而产生这样的气流配置,即禁止流化的粉末或被带在气流中的粉末从药盒排出。 Because of this closeness, the gas flow from the inlet opening across the opening to be administered within the cartridge so as to generate such powder flow configuration, i.e., prohibited or powder fluidized with the gas stream discharged from the cartridge. 以这种方式,在吸入动作期间,进入药盒容器的气流可以完成在药盒容器中的干粉制剂的翻腾,并且靠近药盒的排出口或给药口的流化的粉末可以被进入药盒的入口的气流阻止,从而在药盒内的气流可以被限制从药盒容器排出。 In this manner, during an inhalation maneuver, airflow entering the cartridge container can be done in a dry powder formulation billowing cartridge container, and near the outlet port or the administration of the kit may be fluidized powder into the cartridge preventing gas flow inlet, whereby the gas flow within the cartridge can be discharged from the restricted cartridge container. 由于惯性、密度、速度、电荷相互作用、气流位置的差异,只有特定的颗粒可以通过排出给药口所需的路径。 Since, density, velocity, charge interaction difference inertia, the air flow position, only certain particles may be desired for administration through the discharge port paths. 不能通过出口的颗粒必须继续翻腾直到它们具有适当的重量、电荷、速度或位置。 Not have to continue through the outlet tumbling particles until they have an appropriate weight, charge, velocity or position. 实际上,这种结构可以计量离开药盒的药物的量,并且可以帮助粉末的解聚。 Indeed, such a structure can leave the metered amount of drug cartridge, and can help de-polyethylene powder. 为了进一步帮助剂量排出的流化粉末,可以改变给药口的尺寸和数量。 To further assist the discharge of the fluidized powder dose, may vary in size and number of doses of the mouth. 在一个实施例中,使用了被配置成的圆形两个给药口,每个直径是O. 10cm,并且被布置在靠近容器的中心线的进入孔的附近、朝向空气入口距离中心线约O. 2cm。 In one embodiment, configured to use the administration of two circular mouth, the diameter of each is O. 10cm, and is disposed near the access hole in the vicinity of the center line of the container, about the centerline distance toward the air inlet O. 2cm. 其他实施例可以例如具有包括矩形的各种形状的给药口,其中一个或多个给药口的横截面积从O. 05cm2到约O. 25cm2。 Other embodiments may have, for example, oral administration of various shapes including rectangular, wherein administration of the one or more ports to the cross sectional area from about O. 05cm2 O. 25cm2. 在某些实施例中,给药口的尺寸范围可以是从约O. 05cm到约O. 025cm的直径。 In certain embodiments, oral administration can range in size from about O. 05cm diameter to about the O. 025cm. 可以采用其他形状和横截面积,只要它们在横截面积上与这里给定的值类似即可。 Other cross-sectional shapes and may be employed, so long as they are similar to the values ​​given here to the cross-sectional area. 或者,对于更粘的粉末可以设置更大的给药口横截面积。 Alternatively, for a more viscous powder administration may be provided a larger opening cross-sectional area. 在某些实施例中,在使得给药口的长度相对于宽度保持较大的条件下,给药口的横截面积可以根据粉末块的尺寸相对于给药口(一个或多个)的最小开口尺寸而增加。 In certain embodiments, the oral administration of such a length relative to the width is large minimum holding conditions, oral administration with respect to the cross-sectional area can be administered port (s) according to the block size of the powder opening size increases. 在一个实施例中,进入孔在尺寸上比给药口(一个或多个)的宽度更宽。 In one embodiment, the access hole in size than the administration port (s) of wider width. 在进人孔是矩形的实施例中,空气进入孔包括范围是从约O. 2cm到约药盒的最大宽度的宽度。 In the manhole is rectangular embodiment, air inlet opening comprises a range from about O. 2cm width approximately to the maximum width of the cartridge. 在一个实施例中,高度是约O. 15cm,并且宽度约O. 40cm。 In one embodiment, the height is about O. 15cm, and a width of about O. 40cm. 在替换实施例中,容器可以具有从O. 05cm到约O. 40cm的高度。 In an alternative embodiment, the container may have a height from about O. 05cm to the O. 40cm. 在特定实施例中,容器的宽度可以从约O. 4cm到约I. 2cm,并且高度可以从约O. 6cm到约1.2cm。 In a particular embodiment, the width of the container may range from about O. 4cm to about I. 2cm, and the height can be from about O. 6cm to about 1.2cm. 在实施例中,容器包括一个或多个给药口并且各个给药口具有O. 012cm到约 In an embodiment, the container comprises one or more oral administration and oral administration each having about O. 012cm

O. 25cm的直径。 O. 25cm diameter.

[0127] 在特定的吸入系统中,提供了包括药盒顶部和容器的用于干粉吸入器的药盒,其中药盒顶部配置成相对平整,并且具有一个或多个开口以及具有配置成与容器配合的轨道的一个或多个凸缘;容器具有限定内部体积的内表面,并且可移动地连接到在药盒顶部上的一个或多个凸缘上的轨道,并且通过沿着一个或多个凸缘的轨道移动、可配置成到达保持位置和配药或给药位置。 [0127] In a particular inhalation systems, a cartridge for a dry powder inhaler comprising a cartridge top and a container, wherein the cartridge top configured relatively flat and having one or more openings and a container configured to a mating track or more flanges; container having an inner surface defining an internal volume, and is movably connected to the flange of the rail on the top of one or more of the kit, along with one or more and by the movable flange of the rail, may be configured to reach the holding position and the dispensing or dosing position.

[0128] 在另一个实施例中,吸入系统包括配置成拒绝最小尺寸大于O. 5mm并小于3mm的干粉合成物的粉末团入内的一个或多个排出口。 [0128] In another embodiment, the inhalation system comprises one or more configured to reject into the minimum dimension greater than O. 5mm and 3mm less than the dry powder composition discharge port groups. 在一个实施例中,用于干粉吸入器的药盒包括具有两个或更多个刚性部件的封装;药盒具有一个或多个入口以及一个或多个给药口,其中一个或多个入口具有比给药口的总横截面积大的总横截面积,包括其中一个或多个给药口的总横截面积的范围是从O. 05cm2到约O. 25cm2。 In one embodiment, the kit comprises a dry powder inhaler package having two or more rigid members; kit having one or more inlet ports and one or more administration, wherein the one or more inlets It has a larger total cross sectional area than the total cross sectional area of ​​the administration port, which includes a plurality or range of total cross sectional area of ​​the discharge port is administered from O. 05cm2 to about O. 25cm2.

[0129] 在一个实施例中,用于解聚和分散用于吸入的干粉制剂的方法包括以下步骤:在干粉吸入器中产生空气流,其中干粉吸入器包括嘴部以及具有至少一个入口和至少一个给药口并装有干粉制剂的容器;容器在所述至少一个入口和所述至少一个给药口之间形成空气管道,并且入口将进入容器的空气流的一部分引导至所述至少一个给药口;使空气流翻腾在容器内的粉末以在容器内升起并混合干粉药物来了形成空气流药物混合物;以及加速空气流使其通过所述至少一个给药口排出容器。 [0129] In one embodiment, a method for the depolymerization and dispersing a dry powder formulation for inhalation comprising the steps of: generating an air flow in a dry powder inhaler, wherein the dry powder inhaler includes a nozzle portion and having at least one inlet and at least and a dosing opening of the container containing a dry powder formulation; directing a portion of the air flow inlet and said at least one container forming an air conduit between the at least one opening in the administration, and enters the inlet to the at least one vessel to medication port; churning the air flow within the container and to raise the mixed powder in a dry powder medicament container forming an air flow drug mixture; and accelerate a flow of air through the administration of at least one discharge port of the container. 在该实施例中,由于排出口的横截面积相对于入口的横截面积减小,因此通过给药口的粉末药物能够立即加速。 In this embodiment, since the cross sectional area of ​​the discharge port relative to the inlet cross sectional area is reduced, it is possible to immediately accelerate powdered medicine is administered by mouth. 这种速度的变化可以在吸入期间进一步解聚已流化和雾化的粉末药物。 This change in velocity may further depolymerization streamed and atomized powder medicament during inhalation. 此外,由于在流化的药物中的颗粒或颗粒群的惯性,离开给药口的颗粒的速度并不相同。 Further, due to the inertia in the flow of drug particles or particle groups, the velocity of the particles leaving the administration port is not the same. 在嘴部管道中运动较快的空气流对离开排出后或给药口(一个或多个)的运动较慢的流化粉末施加拖力或剪切力,这可以进一步解聚药物。 Moving faster in the mouth portion of the air flow duct after moving away from the discharge opening or administration (s) is slow fluidized powder is applied drag or shear forces, which may be further depolymerization drugs.

[0130] 由于相对于容器排出口或给药口的横截面积的减小,通过给药口(一个或多个)的粉末药物立即加速,其中排出口或给药口被设计为横截面积小于容器的空气入口。 [0130] Since the reduced cross-sectional area relative to the discharge outlet of the container mouth or administration through the oral administration of an immediate acceleration (s) of powdered medicament, wherein the outlet opening is designed to be administered or cross-sectional area It is smaller than the air inlet of the container. 这种速度的变化可以进一步解聚已流化的粉末药物。 This change in speed may be further depolymerized powdered medicament has been fluidized. 此外,由于在流化的药物中的颗粒或颗粒群的惯性,离开给药口的颗粒的速度与通过给药口的气流的速度并不相同。 Further, due to the inertia in the flow of drug particles or particle groups, the velocity of the particles leaving the administration port and the air flow rate through the administration port is not the same.

[0131] 在这里所述的实施例中,例如通过被施加的流化药物的方向和/或速度的变化,排出给药口的粉末可以进一步加速。 [0131] In the embodiment described herein, for example, by the direction of flow of the drug is applied variations and / or speed, the discharge port the powder administration may be further accelerated. 离开给药口并进入嘴部管道的流化粉末的方向变化能够以相对于给药口的轴线成接近0°到约180°的角度,例如以约90°发生。 Administration into the mouth and away from the direction of the mouth portion of the fluidized powder duct axis with respect to the change can be administered into the mouth to near 0 ° angle of about 180 °, for example at about 90 ° occurs. 流动速度和方向的变化可以进一步解聚通过空气管道的流化粉末。 Changes in flow velocity and direction can be further depolymerized fluidized powder through the air duct. 方向的改变可以通过空气流动管道的几何配置的变化和/或通过利用进入嘴部入口的第二空气流来阻止空气流排出给药口来实现。 Change in direction can be changed by the geometric configuration of the air flow duct and / or to prevent the flow of air discharged by using the administration port into the second air flow inlet mouth is achieved. 由于管道中的横截面积增大,在嘴部管道中的流化粉末在排出之前随着其进入嘴部的口腔放置部分而膨胀并减速。 Because of the pipeline cross-sectional area is increased, fluidized powder in the mouth portion of the pipe as it is placed into the oral cavity of the mouth portion is expanded and decelerated before discharge. 困在粉末块内的气体也会膨胀并且可以帮助打散各个颗粒。 Trapped in the powder block gas will expand and help break up the individual particles. 这是这里所述的实施例的又一解聚机制。 This embodiment is another embodiment of a depolymerization mechanisms described herein. 含有药物的空气流可以进入患者的口腔并且被有效地输送到例如肺循环中。 The air flow containing medicament into the oral cavity of the patient and can be effectively delivered to, for example, the pulmonary circulation.

[0132] 这里所述的各个解聚机制和吸入系统的部分表示使粉末解聚最大化的多阶段方法。 [0132] each section depolymerization mechanisms and inhalation system described herein represents the powder multistage process polymerization solution maximized. 通过使包括管道、药物的一次或多次加速/减速、困住粉末块内的气体的膨胀、粉末性质与吸入器组件材料性质的相互作用(这些是本吸入系统的总体特点)的各个单独的解聚机制的效果最优化,能够得到最大化的粉末解聚和输送。 By including piping, one or more drug acceleration / deceleration, expansion of the gas trapped in the powder cake, powder properties and material properties of the components interact inhaler (which is a general feature of the present inhalation system) of each individual effect depolymerization mechanisms can be optimized to maximize powder delivery and depolymerization. 在这里所述的实施例或者,吸入器设置有刚性空气管道或管道系统以最大化粉末药物的解聚,以使得在重复使用期间从吸入器排放的粉末药物具有连贯性。 In the embodiment or embodiments described herein, the inhaler is provided with a rigid pipe or an air duct system to maximize the depolymerization of the powdered medicine, so that the coherent emission from a powder inhaler during repeated use. 由于本吸入器设置有刚性或保持相同并不发生变化的管道,因此避免了由于与利用泡罩封装的现有技术的吸入器相关的刺穿膜或剥离膜所产生的空气管道构造的变化。 As the inhaler is provided with a rigid pipe or remain the same does not change, thus avoiding a change in the configuration of the air duct due pierceable membrane or film related to the prior art use of inhalers blister package produced.

[0133] 在一个实施例中,提供了在干粉吸入系统中解聚粉末制剂的方法,其包括:将在具有内部体积的容器中的粉末制剂提供到干粉吸入器;使气流进入容器,该容器被配置成引导气流上升、夹带并使干粉制剂流通、直到包含粉末团的粉末制剂足够小以通过一个或多个给药口进入嘴部。 [0133] In one embodiment, there is provided a method of depolymerization powder formulation in a dry powder inhalation system, comprising: a powder formulation in a container having an internal volume of providing to a dry powder inhaler; the flow of air into the container, the container configured to direct the air flow rises, entraining and circulating the dry powder formulation until the powder formulation comprises powder mass small enough to be administered via one or more ports into the mouth. 在本实施例中,所述方法还可以包括使夹带在离开一个或多个给药口并进入嘴部的气流中的粉末团加速的步骤。 In the present embodiment, the method may further comprise leaving entrained in the one or more ports and proceeds to step administering powder mass in the mouth of the air flow accelerated.

[0134] 在这里所述的实施例中,干粉药物在小于约2秒的时间内从吸入器连贯地给出。 [0134] In embodiments, the dry powder medicament are given herein in less than approximately 2 seconds consecutively from the inhaler. 本吸入器系统具有约O. 065到约O. 20( V kPa)/liter每分钟的高阻力值。 The present inhaler system has from about to about O. 065 O. 20 (V kPa) / liter per minute value of the high resistance. 因此在包括药盒的吸入系统中,在DPI 2到20kPa之间的峰值吸入压降产生通过系统的约在7到70L/min的峰值流速。 Therefore, the inhalation system comprises a kit, the peak between 2 to 20kPa DPI suction pressure drop in peak flow of about 7 to 70L / min through the system. 在某些实施例中,吸入器和药盒系统的压力差可以低于2kPa。 In certain embodiments, the inhaler and cartridge system pressure differential may be lower than 2kPa. 对于在I到30mg之间或更大量的粉末填充量,这些流速可导致大于75%的被给出的药盒含量。 For I between 30mg or greater amount of powder filling amount, the content of these flow rates can cause the cartridge to be given more than 75%. 在某些实施例中,由最终用户在单次吸入动作中来实现这些性能特征以产生大于90%的药盒给药比例。 In certain embodiments, by the end user in a single suction action to achieve these performance characteristics to produce a ratio greater than 90% of the kit is administered. 在其他实施例中,由最终用户在单次吸入动作中来实现这些性能特征以产生100%的药盒给药比例。 In other embodiments, by the end user in a single suction action to achieve these performance characteristics to produce a kit dosing ratio of 100%. 在某些实施例中,吸入器和药盒系统被配置成以被输送粉末的连续流、通过从吸入器排放粉末向患者提供单次剂量。 In certain embodiments, the inhaler and cartridge system are configured to be a continuous stream transports the powder, providing a single dose to the patient by discharging powder from the inhaler. 在某些实施例中,可以将吸入系统配置成根据粒径、在使用时以一次或多个粉末排放来输送粉末。 In certain embodiments, the inhalation system may be configured to operate according to the particle size, when used in one or more of the powder discharge conveyor to a powder. 在一个实施例中,提供了用于向患者肺部输送干粉制剂的吸入系统,其包括干粉吸入器,该干粉吸入器被配置成在给药配置中具有从约O. 065到约0.200( V kPa)/liter每分钟的值的范围的总流动阻力的流动管道。 In one embodiment, an inhalation system for delivering a dry powder formulation to a patient's lungs, comprising a dry powder inhaler, a dry powder inhaler which is configured to have from about O. 065 to about 0.200 (V configuration administration the total flow resistance of the flow duct range of values ​​per minute kPa) / liter of. 在本实施例和其他实施例中,吸入系统的总流动阻力在O. 5kPa到7kPa之间的压力差范围内相对恒定。 In this embodiment and other embodiments, the suction system total flow resistance of the pressure difference in the range of between O. 5kPa to 7kPa relatively constant.

[0135] 吸入系统的结构配置允许解聚机制产生大于50%的可呼吸成分和小于5. 8 μ m的颗粒。 Structure Configuration [0135] The suction system allows the depolymerization mechanisms may produce greater than 50% less than the respiratory component and the particles of 5. 8 μ m. 吸入器可以在吸入动作期间排放装在容器中的大于85%的粉末药物。 Inhaler during inhalation operation can be discharged in a container of powdered medicament greater than 85%. 通常,图15中描述的吸入器可以在高达30mg的填充量的情况下、在2kPa到5kPa的压力差下、在小于3秒的时间内排放大于90%的药盒或容器含量。 Typically, the inhaler depicted in Figure 15 may be filled up in the case where the amount of 30mg, under a pressure of 2kPa to 5kPa difference in less than 3 seconds, the discharge vessel is greater than or kit content of 90%.

[0136] 在另一实施例中,本系统具有性能的下限。 [0136] In another embodiment, the present system performance with a lower limit. 该性能限制是基于达到中止特定粒径分布的这里所述的干粉吸入来指定的。 This limit is based on the performance of a dry powder inhaler described herein to achieve a specific particle size distribution of the suspension to specify. 可形成PIP和AUC的图表,其中存在其中对于给定的AUC值、PIP值在物理上不可能得到的三角区。 Chart PIP and AUC may be formed in which there is, for a given triangle wherein AUC value, the value of PIP physically impossible to get. 然而,基于表示通过标准的水平和竖直线可以形成可接收区域。 However, based on the receiving area representation may be formed by standard horizontal and vertical lines. 这里所述的吸入系统具有约2kPa的PIP和至少约I. 0、1. I或 Inhalation system described herein and having a PIP about 2kPa least about I. 0,1. I or

I. 2kPa*sec的AUC的可接受性能的下限。 The lower limit of acceptable performance AUC of I. 2kPa * sec.

[0137] 在其他实施例中,对于AUC存在下限和上限。 [0137] In other embodiments, an upper limit and a lower limit for the AUC. 例如,AUC的范围可以是从约I. O到15kPa*sec、从约I. O 到约10kPa*sec、从约I. I 到约15kPa*sec、从约I. 2 到约10kPa*sec、从约I. 2到约15kPa*sec或者从约I. 2到约10kPa*seco For example, AUC may range from about I. O to 15kPa * sec, from about I. O to about 10kPa * sec, from about I. I to about 15kPa * sec, from about I. 2 to about 10kPa * sec, I. 2 from about 15kPa * sec to about or from about I. 2 to about 10kPa * seco

[0138] 在另一实施例中,通过提供高阻力的装有一剂干粉药物的干粉吸入器、来实现利用高阻力干粉吸入器的一剂充分解聚的干粉药物;在2秒内利用达到至少2kPa的峰值吸入压力的足够的力、从吸入器吸入;以及产生至少约I. O、I. I或I. 2kPa*秒的、吸入压力-时间曲线的第一秒曲线下面积(AUCch1sJ ;其中排出粉末的VMGD(x50)小于约5um。在某些实施例中,患者在两(2)秒内(PIP2秒)施加大于等于2kPa小于等于15或20kPa的峰值吸入压力。在另一实施例中,干粉药物包括这样的微粒,其中排出粉末的中值粒径VMGD(x50)不大于当吸入器被最佳使用时的中值粒径的I. 33倍。在本实施例和其他实施例中,由患者的最佳吸入器使用是当患者在两(2)秒内(PIP2秒)施加约6kPa的峰值吸入压力时。最佳使用还可以被认为通过实现约28. 3L每秒的流速来实现。类似的最佳使用可以反映例 [0138] In another embodiment, by providing a high resistance to a drug with a dry powder inhaler, be implemented with a high resistance dry powder inhaler is a dry powder pharmaceutical sufficient depolymerization; in use at least 2 seconds 2kPa sufficient peak force of the suction pressure, suction from the suction device; and generating at least about I. O, I I, or I. 2kPa * sec, a suction pressure - the area (AUCch1sJ time curve of the first curve seconds;. wherein discharging the powder VMGD (x50) is less than about 5um. in certain embodiments, the patient is applied to the peak value less than or equal to 2kPa 20kPa 15 or the suction pressure. in another embodiment, the (second PIP2) within two (2) seconds , dry powder medicament comprising such particles, wherein the powder discharging median diameter VMGD (x50) when the inhaler is not more than 33 times the median particle size is best used when I.. in this embodiment and other embodiments , when used by a patient the inhaler is preferred when (PIP2 second) peak of about 6kPa applied suction pressure in patients within two (2) seconds. use may also be considered the best by implementing the flow rate per second to about 28. 3L implementation. similar cases may reflect the best use 在USP〈601>中所指定的空气动力学粒径测试的标准测试条件。 In USP <601> specified aerodynamic diameter test standard test conditions.

[0139] 在某些实施例中,高阻力干粉吸入器包括一剂干粉药物,其由患者在2秒内利用达到至少2kPa的峰值吸入压力的足够的力(或作用力)来吸入;以及产生吸入压力与时间曲线的至少约I. O、I. I或I. 2kPa*秒的第一秒的曲线下面积(AUCch1sJ ;其中大于75%的干粉药物作为粉末颗粒被从吸入器排放或排出。在某些实施例中被排出颗粒的VMGD小于约5微米。 [0139] In certain embodiments, the high resistance dry powder inhaler comprising a dry powder medicament, which is utilized by the patient within 2 seconds sufficient to achieve a peak force of at least 2kPa suction pressure (or force) to suction; and generating suction pressure versus time curve at least about I. O, I, or I. the area under the curve I first second 2kPa * sec (AUCch1sJ;. wherein more than 75% of the dry powder medicament as the powder particles are discharged from the inhaler or discharged. in certain embodiments, the particles discharged VMGD less than about 5 microns.

[0140] 通过提供高阻力的装有一剂干粉药物的干粉吸入器、来实现利用高阻力干粉吸入器的一剂充分解聚的干粉药物;在2秒内利用达到至少2kPa的峰值吸入压力的足够的力、从吸入器吸入;以及产生至少约I. O、I. I或I. 2kPa*秒的、吸入压力-时间曲线的第一秒曲线下面积(AUCch1sJ ;其中排出粉末的VMGD(x50)小于约5um。在另一实施例中,干粉药物包括这样的微粒,其中排出粉末的中值粒径VMGD (x50)不大于当吸入器被最佳使用时的中值粒径的I. 33倍。 [0140] By providing a high resistance with a dry powder medicament in a dry powder inhaler, be implemented with a high resistance dry powder inhaler is a dry powder pharmaceutical sufficient depolymerization; use peaked at least 2kPa within 2 seconds suction pressure sufficient force, sucked from the inhaler; and generating at least about I. O, I I, or I. 2kPa * sec, a suction pressure - the area under the time curve of the first curve seconds (AUCch1sJ;. wherein the powder discharging VMGD (x50) less than about 5um. in another embodiment, the dry powder medicament comprising such particles, wherein the powder discharging median diameter VMGD (x50) is not larger than I. when the median particle size when the inhaler is used 33 times best .

[0141] 虽然本发明主要被描述为呼吸供能的,但在某些实施例中,吸入器可以设置有用于产生解聚所需的压力差和输送干粉制剂的能源。 [0141] While the invention has been described primarily respiratory energized, in certain embodiments, the inhaler may be provided for generating a pressure difference and the delivery of dry powder formulations of the required energy depolymerization. 例如,吸入器可以采用气体动力源,诸如存储在诸如来自可设置在空气入口处的氮罐等的压缩气体动力源等。 For example, the inhaler may be employed a gas power source, such as a power source in the gas inlet of the compressed air tanks, etc., such as nitrogen may be provided from other storage. 可以设置取间隔的装置来捕获羽流以使得患者可以舒适的速度吸入。 Fetch means may be provided to capture the plume interval so that the patient can comfortably speed suction.

[0142] 在这里所述的实施例中,吸入器可设置为重复使用的吸入器或一次性使用的吸入器。 [0142] In the embodiment described herein, the inhaler may be provided as a reusable inhaler inhaler or disposable. 在替换实施例中,相似的解聚原理可适用于多次剂量吸入器,在多剂量吸入器中,吸入器可在单个托盘中包括多个例如类似于药盒的结构,并且可根据需要拨出单次剂量。 Embodiment, a similar principle can be applied to a depolymerization multiple dose inhalers In an alternative embodiment, in multi-dose inhaler, the inhaler may comprise a plurality of similar structures, for example, in a single cartridge tray, and may be required to dial a single dose. 在本实施例的变体中,多次剂量吸入器可被配置成提供例如按天、按星期或按月供给的足够剂量的药物。 In a variant of the embodiment according to the present embodiment, multiple dose inhalers can be configured to provide a daily, weekly or monthly supply a sufficient dose of the drug for example. 在所述实施例的多次剂量实施例中,优化了最终用户的便利性。 Example of multiple doses in the embodiment, to optimize end-user convenience. 例如,在膳食疗法中,利用配置成在单个设备中提供用于7天疗程的剂量的系统,实现早餐、午餐和晚餐给药。 For example, in the diet therapy, using the apparatus configured to provide a single dose of the treatment system for 7 days, to achieve breakfast, lunch, and dinner dosing. 通过配置有指示天和剂量(例如第三天(D3)、午饭(L))的指示机构的系统,提供了其他的最终用户便利性。 By configuring the dose indicating days (e.g., third (D3), lunchtime (L)) of the system indicating means provides another end-user convenience.

[0143] 在一个实施例中,干粉药物可包括例如,二酮哌嗪和药用活性成分。 [0143] In one embodiment, the dry powder medicament may comprise, for example, a diketopiperazine and a pharmaceutically active ingredient. 在本实施例中,药用活性成分或活性剂根据被治疗的疾病或状况、可以是任何类型。 In the present embodiment, the pharmaceutically active ingredient or an active agent according to the disease or condition being treated, and may be of any type. 在另一实施例中,例如,二酮哌嗪可以包括对形成颗粒、微粒等有效用的对称分子和不对称二酮哌嗪,其可用作将活性剂输送到身体的目标位置的载体系统。 In another embodiment, for example, may comprise diketopiperazine form particles, fine particles with effective molecular symmetrical and asymmetrical diketopiperazine, which can be used to deliver an active agent to a target position vector systems of the body . 术语“活性剂”这里指代要封装、加入、结合、络合或夹带或吸入到二酮哌嗪制剂上的诸如蛋白质、肽或生物分子等治疗药物或分子。 The term "active agent" herein refers to packaging, added, incorporated, complexed, or entrained or drawn into or therapeutic drug molecules such as proteins, peptides or biological molecules on the diketopiperazine formulation. 药物输送系统可用于输送具有治疗、预防或诊断作用的生物活性剂。 Drug delivery system may be used for delivery of therapeutic, prophylactic or diagnostic agent, a bioactive effect.

[0144] 克服了诸如药物不稳定和/或吸收不良等制药领域中的问题、已被用于产生微粒的一类药物输送剂是2,5_二酮哌嗪。 [0144] overcomes the problems of instability, such as drugs and / or malabsorption in the pharmaceutical art, it has been used to produce particles of a class of drug delivery agents are 2,5_ diketopiperazine. 2,5_二酮哌嗪通过下面所示的一般化学结构式I的化合物来表示,其中在位置I和4的环原子E1和E2是O或N以分别产生二酮吗啉和二恶烷二酮的取代类似物,并且位于位置3和位置6侧链R1和R2中的至少一者包含羟酸(羟酸盐)组。 2,5_ diketopiperazine compound represented by the general chemical structure of Formula I shown below, in which position I and E1 and E2 4 ring atoms are O or N, respectively, to produce a morpholine dione dioxane and two ketones substituted analogs, and is located (hydroxy acid) comprises a set of at least one hydroxy acid positions 3 and 6 positions of the side chains R1 and R2. 根据化学结构式I的化合物包括但不限于二酮哌嗪、二酮吗啉(diketopiperazines)和二酮二氧杂环乙烧(diketomorpholines)及其替代类似物。 Compounds according to formula I include but are not limited to diketopiperazine, diketomorpholine (diketopiperazines) -dione and burn dioxin acetate (diketomorpholines) and its alternatives like.

[0145] [0145]

Figure CN102985125AD00261

[0146] 这里所使用的“二酮哌嗪”或“DKP”包括落在通用化学结构式I范围内的二酮哌嗪及其约学上可接受的盐、衍生物、替代物和修改物。 [0146] As used herein, "diketopiperazine" or "the DKP" includes diketopiperazines fall within the general scope of formula I and their pharmaceutically acceptable salts about, derivatives, alternatives and modifications thereof.

[0147] 这些2,5- 二酮哌嗪已经示出了在药物输送尤其是那些承载酸性Rl和R2组的药物输送中有效(参见例如题为“Self Assembling Diketopiperazine Drug DeliverySystem” 的美国专利No. 5, 352, 461,题为“Method For Making Self-AssemblingDiketopiperazine Drug Delivery System” 的美国专利No. 5,503,852,题为“Microparticles For Lung Delivery Comprising Diketopiperazine,,的美国专利No. 6,071,497,以及题为“6,331,318”的美国专利No. 6,331,318,对于以上各个专利的教·导的关于二酮哌嗪以及二酮哌嗪媒介的药物输送内容、通过引用全部结合于此)。二酮哌嗪可形成为药物吸附微粒。药物和二酮哌嗪的这种结合可给予改善的药物稳定性和/或吸附特性。这些微粒可通过各种分配路径来提供。这些药物可以作为干粉通过吸入到呼吸系统的具体部位包括肺部来输送。 [0147] These 2,5 diketopiperazines have been shown in U.S. Pat drug delivery, especially those carrying an acidic drug delivery Rl and R2 groups are effective (see, e.g., entitled "Self Assembling Diketopiperazine Drug DeliverySystem" of No. 5, 352, 461, entitled "Method For Making Self-AssemblingDiketopiperazine Drug Delivery System" of U.S. Patent No. 5,503,852, entitled "Microparticles For Lung Delivery Comprising Diketopiperazine ,, U.S. Patent No. 6,071, 497, and US Patent No. entitled "6,331,318" of 6,331,318 for each of the above patents teach about drug-mediated diketopiperazine and diketopiperazine media content delivery, by reference all incorporated herein). diketopiperazine microparticles adsorb a drug may be formed. this combination of a drug and a diketopiperazine can be administered to improve drug stability and / or adsorption characteristics of these particles may be provided by a variety of dispensing path these drugs can be delivered by inhalation to specific parts of the respiratory system including the lungs as a dry powder.

[0148] 延胡索酰二酮哌嗪(二_3,6-(N-延胡索酰-4-氨基可基)-2,5-二酮哌嗪;FDKP) [0148] fumaric acid diketopiperazine (two _3,6- (N- fumaric acid may be 4-amino-yl) -2,5-diketopiperazine; the FDKP)

是用于肺部应用的一种优选的二酮哌嗪: Is one preferred diketopiperazine for pulmonary applications of:

[0149] [0149]

Figure CN102985125AD00262

[0150] FDKP提供了有利的微粒基质,这是由于其在酸中溶解度较低但是但在中性或碱性溶液中易于溶解。 [0150] FDKP provides a beneficial microparticle matrix, due to its lower solubility, but it readily soluble in a neutral or alkaline solution in an acid. 这些性质使得FDKP在酸性条件下结晶并且晶体自组装形成颗粒。 These properties allow FDKP crystallize under acidic conditions and the crystals self-assemble into particles. 该颗粒在PH是中性的生理条件下容易溶解。 The particles are easily dissolved in the PH neutral under physiological conditions. 在一个实施例中,这里所公开的微粒是装载有诸如胰岛素等的活性剂的FDKP微粒。 In one embodiment, the microparticles disclosed herein are FDKP microparticles loaded with an active agent such as insulin or the like.

[0151] FDKP是相对于在二酮哌嗪环上的取代碳的取代物的排列具有顺式和反式异构体的手性分子。 [0151] FDKP is arranged relative to the substituted carbon substituent at the diketopiperazine ring has cis and trans isomers of chiral molecules. 如在题为“Diketopiperazine microparticles with defined isomercontents”的美国专利申请公开No. 2010/0317574中所描述的,通过将异构体含量限制为约45%至65%的顺式可得到更强的空气动力学性能和颗粒形态的连贯性。 As described in U.S. Patent No., entitled "Diketopiperazine microparticles with defined isomercontents" Application Publication No. 2010/0317574 described, by limiting the isomer content of about 45% to 65% more available cis aerodynamic coherence properties and particle morphology. 在分子的合成和再结晶中可控制异构体比例。 Synthesis and recrystallization of the molecule can control the isomer ratio. 例如在从端羟基去除保护基期间,接触基促进导致外消旋作用的环差向异构作用。 For example during the removal of the protecting group from the terminal hydroxy group, the contact group cause racemization promoting effect epimerization ring. 然而,在该步骤中增加甲醇溶剂的含量导致反式异构体的含量增力口。 However, increasing the content of methanol as solvent in this step results in the trans isomer content of booster port. 反式异构体比顺式异构体更不易溶解,并且在再结晶期间控制温度和溶剂成分,可用于促进或减少在此步骤中的反式异构体的富集。 Trans isomer be less soluble than the cis isomer, and controlling the temperature and solvent composition during recrystallization can be used to promote or reduce trans-isomer enriched in this step.

[0152] 具有直径约O. 5微米到约10微米之间的微粒能够成功地通过大多数自然屏障而到达肺部。 [0152] O. particles having a diameter of approximately between 5 microns to about 10 microns can be most successfully through natural barriers and reach the lungs. 通过咽喉之交需要小于约10微米的直径,并且避免被呼出出则需要大于等于约O. 5微米的直径。 By the turn of the throat requires less than about 10 microns in diameter, and is required to avoid being exhaled a diameter greater than or equal to about O. 5 microns. 具有在约35到约67m2/g的比表面积(SSA)的二酮哌嗪微粒呈现出有益于向肺部输送药物的特性,诸如改善的空气空力学性能和改善的药物吸附性等。 Having about 35 to about 67m2 / g of specific surface area (SSA) of diketopiperazine microparticles exhibit beneficial to delivery of drugs to the lung characteristics, improved mechanical properties and improved air space adsorbent such as a drug.

[0153] 如在题为“Diketopiperazine microparticles with defined specific surfaceareas”的PCT公开No. W02010144789中所描述的,FDKP晶体的尺寸分布和形状受到新晶体的成核和已有晶体的生长之间的平衡的影响。 [0153] The entitled "Diketopiperazine microparticles with defined specific surfaceareas" PCT Publication No. W02010144789 described, FDKP crystal size distribution and the shape of the balance between growth of new crystals by nucleation and existing crystals influences. 这两种现象都在很大程度上取决于溶液中的浓度和过度饱和。 These two phenomena are highly dependent on the solution concentration and over-saturation. FDKP晶体的特征尺寸是成核和生长的相对比例的指示。 Feature size is to indicate the FDKP crystal nucleation and growth relative proportions. 当成核占优势时,形成很多晶体但是这些晶体都相对较小,这是因为都他们针对溶液中的F进行竞争。 When the nucleation dominant, the formation of many crystals but these crystals are relatively small, it is because they are competing for the solution of F. 当生长占优势时,存在较少的竞争晶体并且晶体的特征尺寸较大。 When growth dominates, there are fewer competing crystals and the characteristic size of the crystals larger.

[0154] 结晶化很大程度上取决于过度饱和,过度饱和又很大程度上取决于在原料流中的成分的浓度。 [0154] crystallization depends largely on supersaturation, and depends largely on the supersaturation concentration of the component in the feed stream. 较高的过度饱和与很多小晶体的形成有关;较低的过度饱和产生较少的较大的晶体。 High supersaturation with many small crystals are formed about; lower supersaturation produces fewer larger crystals. 关于过度饱和:1)增大FDKP浓度提高过度饱和;2)增大氨的浓度将系统转换到更高的pH,提高平衡溶解度并降低过度饱和;以及3)增大醋酸浓度通过将端点转移到平衡溶解度较低的较低PH而提高过度饱和。 About supersaturation: 1) increasing the FDKP concentration was increased supersaturation; 2) increasing the concentration of ammonia to convert the system to a higher pH, to improve the equilibrium solubility and reduce supersaturation; and 3) increasing the concentration of acetic acid will be transferred through the end point lower equilibrium solubility of low PH and improve the over-saturation. 降低这些组分的浓度导致相反的效果。 Reducing the concentration of these components results in the opposite effect.

[0155] 温度通过其对FDKP溶解度和FDKP的晶体成核和生长的动力学的影响而影响FDKP微粒形成。 [0155] Temperature their nucleation and growth kinetics of FDKP solubility and the influence of FDKP crystals formed by FDKP microparticles. 在较低的温度下,形成具有较高比表面积的较小晶体。 At lower temperatures, the formation of smaller crystals having a high specific surface area. 这些颗粒的悬浮液呈现出较高的粘性,其指示了较强的颗粒间吸引力的。 The suspension of these particles exhibit high viscosity, which indicates a strong inter-particle attraction. 在包括这里所述的吸入器系统的各种吸入器系统的情况下,从约12°C到约26°C的温度范围产生具有可接受的(或者较好的)空气动力学性能的颗粒。 In the case of the inhaler includes various systems described herein inhaler system, to a temperature range of about 26 ° C to produce an acceptable (or better) aerodynamic performance particles of from about 12 ° C.

[0156] 这些本发明的设备和系统对具有较宽范围的特性的粉末的肺部输送有效。 [0156] These devices and systems of the present invention on lung powders having a wide range of properties of active transport. 本发明的实施例包括如下系统,其包括吸入器、集成的或可安装的单位剂量药盒以及限定(一个或多个)特征(提供性能的改善或最佳范围)的粉末。 Embodiments of the present invention comprises systems, comprising a powder inhaler, or an integrated cartridge mounting unit dosage and define (one or more) features (properties provide improved or optimal range). 例如,设备包括有效的解聚装置并且因此能够有效地输送粘性粉末。 For example, the apparatus comprising means effective depolymerization and thus can efficiently deliver cohesive powders. 这与其他人基于自由流动或流动最优化的颗粒来寻求发展干粉吸入系统的方法不同(参见例如美国专利No. 5,997,848以及No. 7,399,528,美国专利申请No. 2006/0260777 ;以及Ferrari 等人的AAPS PharmSciTech 2004 ;5(4)第60 章)。 This method based on the free movement or flow optimized particle with others to seek the development of dry powder inhalation system is different (see, eg, US Patent No. 5,997,848 and No. 7,399,528, US Patent Application No. 2006 / 0,260,777; and Ferrari et al, AAPS PharmSciTech 2004; 5 (4) Chapter 60). 因此,实施例包括加上了粘性粉末的系统。 Thus, embodiments of the system comprising adding a cohesive powders.

[0157] 粉末的粘结性可根据其流动性或与形状和诸如皱褶状态等的不规则的评估来评价。 [0157] Powder adhesion may be evaluated according to the evaluation of its irregular shape, such as wrinkles and state of flowability or the like. 如在美国药典USP 29,2006部分1174中所讨论的,在制药领域中通常使用四种技术来评估粉末流动性:堆角;可压缩性(卡尔)指数和豪斯纳比;流经孔口;以及剪切室方法。 As in the US Pharmacopeia USP 29,2006 portion 1174 as discussed above, in the pharmaceutical art generally uses four techniques to assess powder flowability: angle of repose; compressibility (Carr) index and Hausner ratio; flows through the orifice ; and a shear cell methods. 对于后面的两种方法,由于方法的多样性还没有开发通用标准。 For the latter two methods, due to the diversity of methods have not developed common standards. 流经孔口可用于测量流速或者用于确定允许流动的标准直径。 Flowing through the orifice can be used to measure flow rate or to allow the standard to determine the diameter of the flow. 相关变量是孔口的形状和直径,粉末层的直径和高度以及构成装置的材料。 Is highly dependent variable aperture diameter and shape and diameter, and the material constituting the powder layer device. 剪切室设备包括圆柱形、环形和平面类型并且提供很大程度的实验控制。 Shear cell apparatus comprises a cylindrical, annular, and planar type and provides a great degree of experimental control. 这两种方法的任一者的设备和方法描述是非常关键的,但是尽管缺乏通用标准,它们仍然成功地用于提供粉末流动性的定性和相对表征。 The method and apparatus according to any one of the two methods described is crucial, but despite the lack of common standards, they are still successfully used to provide qualitative and relative flowability of a powder characterization.

[0158] 堆角被确定为通过材料的圆锥状堆相对于材料已被倒在上面的水平基底而假设的角度。 [0158] the angle of repose is determined by the conical pile material with respect to the poured material has been assumed above horizontal base angle. 豪斯纳比是用未处理的体积除以振实体积(即在振实作业以后体积不再变化的体积)或者用振实密度除以堆密度。 Hausner ratio is divided by the tapped volume of the untreated volume (i.e. the volume after tapping operation not change volume) or with a tap density divided by the bulk density. 可压缩性系数(Cl)可由豪斯纳比(HR)计算: Compressibility coefficient (Cl) by the Hausner ratio (HR) calculated:

[0159] Cl = 100x(l_(l/HR)) [0159] Cl = 100x (l_ (l / HR))

[0160] 尽管在实验方法上有变化,但对于堆角、可压缩性指数和豪斯纳比的流动性的通用公认标准已被出版(Carr, RL, Chem. Eng. 1965,72 :163-168)。 [0160] Although there are variations in the experimental procedure, but the angle of repose, compressibility index and Hausner ratio flowability common accepted standards have been published (Carr, RL, Chem Eng 1965,72:.. 163- 168).

Figure CN102985125AD00281

[0163] 输送设备制造商协会(CEMA)规范提供了堆角的稍微不同的描述。 [0163] Manufacturers Association delivery device (of CEMA) specification provides a description of the stack slightly different angle.

[0164] [0164]

Figure CN102985125AD00282

[0165] 具有根据上表的、优秀或良好的流动特性的粉末在粘结性方面可被定性为非粘性或微粘性,并且具有较弱流动性的粉末被定性为粘性,并且在适度粘性(对应于好或尚可的流动特性)和高粘性(对应于任意程度的较差的流动特性)之间进一步区分。 [0165] According to the table having, excellent or good powder flow characteristics in terms of adhesion can be classified as non-tacky or slightly tacky, and has less fluidity powder is characterized as a viscous, moderately viscous and ( further distinguish between the corresponding good or fair flow characteristics) and high viscosity (corresponding to any degree of poor flow properties). 在根据CEMA标准来评估时,具有>30°的堆角可被认为是粘性的并且大于>40°的粉末被认为是高粘性的。 When evaluated according to standard CEMA, with> 30 ° angle stack it may be considered to be viscous and is> 40 ° powder is considered highly viscous. 在这些等级中的各个等级中的粉末或其组合构成本发明的不同实施例的方面。 In each of these levels in the level of a powder or a combination thereof in the aspects of the various embodiments of the present invention. [0166] 粘结性与皱褶状态相关联,皱褶状态是颗粒表面的不规则状态的量度。 [0166] adhesion and wrinkling associated with the state, the state is a measure of irregularity folds the particle surface. 皱褶状态是颗粒的实际比表面积与等效球体的比表面积的比: Wrinkled state is the actual specific surface area than the equivalent sphere surface area ratio of particles:

[0167] [0167]

Figure CN102985125AD00291

[0168] 本领域中还已知诸如空气渗透测粒法等皱褶状态的直接测量方法。 [0168] Also known in the art, such as direct measurement of the air permeability measured wrinkle state granulation method and the like. 大于等于2的皱褶状态已被与增大的粘结性相关联。 Than 2 folds bonded phase state has been associated with increased. 应该记住,粒径也影响流动性,因此较大的颗粒(例如100微米量级)尽管皱褶状态有些上升但可以具有合理的流动性。 It should be remembered, the particle size also affects flowability, thus larger particles (e.g., 100 microns) although some wrinkling state but reasonable increase in flowability. 然而,对于诸如直径为1-3微米的初级颗粒等、用于输送到深肺中的颗粒,即使是小幅上升的或2-6皱褶状态也是粘性的。 However, as for the primary particles of 1-3 microns in diameter, for delivery to the deep lung for particles, or even a slight increase in viscosity is 2-6 folds state. 高粘性粉末可具有> 10的皱褶状态(见下面的示例A)。 Powder may have high viscosity> wrinkle state 10 (see example below A).

[0169] 下面的很多示例涉及包括FDKP的干粉的使用。 [0169] The following example relates to a use of a lot of FDKP dry powder. 组成颗粒是晶体板大的自组装聚合体。 Particles are composed of large crystal polymer sheet self-assembly. 由具有板状表面的颗粒构成的粉末已知通常具有较差的流动性,即,是粘性的。 The powder particles composed of a plate having a surface generally known to have poor flowability, i.e., are sticky. 实际上光滑的球形颗粒通常具有最好的流动性,流动性通常随着颗粒变成椭圆形、具有锋利的边缘、变成基本上二维的和不规则的形状、具有不规则的联锁形状或者是纤维状的而变差。 Indeed smooth spherical particles generally have the best flowability, with flowability generally elliptically-shaped particles having sharp edges, become substantially two dimensional and irregularly shaped, have irregular interlocking shapes or fibrous deteriorated. 不期望进行限制地,申请人目前认为,FDKP微粒的晶体板能够交错和互锁、增强了包含FDKP微粒的散装粉末的粘结性(流动性的反面)并额外地使得粉末比较低粘性的粉末更难以解聚。 Limitation is not desired, the Applicant presently considered, the crystal plate FDKP microparticles can be interleaved and interlocking, cohesiveness enhanced bulk powder comprising FDKP microparticles (flowability reverse) and additionally a relatively low viscosity of the powder powder more difficult to depolymerization. 此外,影响颗粒的结构的因素能够影响空气动力学性能。 In addition, factors affect the particle structure can affect aerodynamic performance. 已经观察到随着颗粒的比表面积增加到超过作为可呼吸成分测量的阈值,其空气空力学性能倾向于减小。 As it has been observed that the threshold value is increased beyond a specific surface area of ​​particles measured as a respiratory component, which tends to decrease the mechanical properties of the air space. 此外,FDKP在哌嗪环中具有两个手性碳原子,使得N-延胡索酰-4-氨基丁基臂可以是相对于环平面的顺式或反式结构。 Further, the FDKP has two chiral carbon atom in the piperazine ring, so that the fumaric acid-4-amino-butyl N- arm relative to the plane of the ring may be cis or trans configuration. 已经观察到,随着在制造微粒中使用的FDKP的反式-顺式比例远离包括外消旋混合物的最佳范围,可呼吸成分减小,并且在更加偏离优选范围时、SEM中的颗粒的形貌变得明显不同。 It has been observed, as used in the manufacture of trans FDKP microparticles of - cis ratio range including the best away from racemic mixtures, respiratory component can be reduced, and further when the deviation from the preferred range, SEM of the particles It becomes significantly different topography. 因此本发明的实施例包括加上了具有在优选范围内的比表面积的二酮哌嗪粉末的设备、以及加上了具有在优选范围内的顺式-反式异构体比例的FDKP粉末的设备的系统。 Thus embodiments include adding a device having a specific surface area within the preferred range of diketopiperazine powder of the present invention, and together with the cis in the preferred range - trans isomer ratio of FDKP powder system equipment.

[0170] 未经修改的或者含有例如胰岛素等药物的FDKP微粒构成高粘性粉末。 [0170] FDKP microparticles or unmodified containing drugs such as insulin and the like constituting the high cohesive powders. 已经测量了FDKP微粒具有I. 8的豪斯纳比,47%的可压缩性指数以及40°的堆角。 FDKP microparticles have been measured I. 8 having a Hausner ratio of 47% compressibility index and the angle of repose of 40 °. 已经测量了加载了胰岛素的FDKP微粒(TFfHNOSPHERE⑩胰岛素;德州仪器;MannKind公司;瓦伦西亚;加拿大)具有I. 57的豪斯纳比,36%的可压缩性指数以及50° ±3°的堆角。 Have been measured insulin loaded FDKP microparticles (TFfHNOSPHERE⑩ insulin; TI;, MannKind Corporation; Valencia; Canada) I. 57 having a Hausner ratio of 36% and a compressibility index of 50 ° ± 3 ° stack angle. 此外,在标准孔口测试中,估计出为了在重力下实现流动,将需要2-3英尺(60-90cm)量级的孔口直径(假设床体高度是2. 5英尺;压力增大则需要增大的直径尺寸)。 Further, the aperture in the standard tests, in order to achieve the estimated flow under gravity, will require 2-3 feet (60-90cm) orifice diameter of the order (assuming that the bed height of 2.5 feet; increased pressure is necessary to increase the diameter size). 在相似的条件下,自由流动的粉末将需要仅l_2cm量级的孔口直径(Taylor,MK等人AAPS PharmSciTech 1,第 Under similar conditions a free flowing powder would require an orifice diameter on the order of only l_2cm (Taylor, MK et al. AAPS PharmSciTech 1, the first

18 章)。 Chapter 18).

[0171] 此外,在实施例中,本发明的吸入系统包括用于解聚所提供的粘性粉末的干粉吸入器和药盒,其中粘性粉末包括具有从16至50的卡尔指数的粘性干粉。 [0171] Further, in the embodiment, the inhalation system of the invention comprises means for providing a viscous depolymerization dry powder inhaler and powder cartridge, which comprises a cohesive powders from a powder having a viscosity index of 16 to 50. Carr's. 在一个实施例中,干粉制剂包括二酮哌嗪(包括FDKP)以及含有诸如胰岛素、GLP-1、甲状旁腺激素、调酸素以及本公开其他地方体积的其他内分泌激素等的内分泌激素的缩氨酸或蛋白质。 In one embodiment, the dry powder formulations comprising diketopiperazine (including the FDKP) and condensing the ammonia-containing hormone such as insulin, GLP-1, parathyroid hormone, oxyntomodulin, and elsewhere in the present disclosure volume of other endocrine hormone acid or protein.

[0172] 具有直径约O. 5微米到约10微米之间的微粒能够成功地通过大多数自然屏障而到达肺部。 [0172] O. particles having a diameter of approximately between 5 microns to about 10 microns can be most successfully through natural barriers and reach the lungs. 通过咽喉之交需要小于约10微米的直径,并且需要大于等于约O. 5微米的直径来避免被呼出。 By the turn of the throat it requires less than about 10 microns in diameter, and requires greater than or equal to about O. 5 microns in diameter to avoid being exhaled. 这里所公开的实施例显示,具有在约35到约67m2/g的SSA的二酮哌嗪微粒呈现出有益于向肺部输送药物的特性,诸如改善的空气空力学性能和改善的药物吸附性 The disclosed embodiments show embodiments herein, diketopiperazine microparticles having from about 35 to about 67m2 / g SSA exhibits the beneficial characteristics of delivering a medicament to the lungs, such as improved mechanical properties and air space improved drug adsorption

坐寸ο Sit inch ο

[0173] 这里还公开了具有约45%至约65%的比表面积的FDKP微粒。 [0173] Also disclosed herein are FDKP microparticles having about 45% to about 65% of the specific surface area. 在该实施例中,微粒提供了改善的能够飞行的性质。 In this embodiment, the microparticles provide improved properties can fly.

[0174] 在一个实施例中,还提供了用于输送可吸入干粉的系统,所述系统包括:a)包含·药物的粘性粉末;以及b)吸入器,其包括限定用于容纳粉末的内部体积的封装,该封装包括气体入口和气体出口,其中入口和出口被布置成使得通过入口流入到内部体积中的气体被引导至朝向出口流动。 [0174] In one embodiment, also provides a system for the delivery of inhalable dry powder, said system comprising: a) a cohesive powder comprising a medicament ·; and b) an inhaler comprising a powder for housing defining an internal volume of the package, the package comprising a gas inlet and a gas outlet, wherein the inlet and the outlet are arranged such that the gas flows into the internal volume is directed to flow through the inlet toward the outlet. 在实施例中,该系统对于解聚具有从18至50的卡尔指数的粘性粉末有用。 In an embodiment, the system is useful for the depolymerization having a cohesive powders from a Carr index of 18 to 50. 当粘性粉末具有从30°到55°的堆角时,该系统对输送粉末有用。 When the cohesive powder has a bulk angle from 30 ° to 55 °, the system is useful for powder delivery. 粘性粉末可通过对于漏斗流< 3. 2英尺的或对于集流< 2. 4英尺的标准孔口尺寸、> 2的皱裙状态来描述。 Cohesive powders can flow to the hopper <3.2 feet for the collector or <standard orifice size of 2.4 feet,> wrinkled skirt 2 is described by state. 示例性粘性粉末颗粒包括由FDKP晶体构成的颗粒,其中FDKP异构体的比例在反式:顺式50%到65%的范围内。 Exemplary cohesive powder particles include particles composed of FDKP crystals wherein the ratio of FDKP trans isomer in: the range of 50% cis and 65% by weight.

[0175] 在另一实施例中,吸入系统可包括吸入器,该吸入器包括嘴部及其上,其对吸入器施加> 2kPa的压降以产生从嘴部排出的颗粒羽流,其中50%的被排出颗粒具有< 10微米的VMGD,其中50%的被排出颗粒具有< 8微米的VMGD,或者其中50%的被排出颗粒具有(4微米的VMGD。 [0175] In another embodiment, the inhalation system can comprise an inhaler, the inhaler includes a nozzle portion and on which is applied to the inhaler> 2kPa pressure drop to generate a plume of particles is discharged from the mouth portion, wherein 50 % of the particles have been discharged VMGD <10 microns, 50% of the particles have been discharged VMGD <8 microns, or wherein 50% of the particles having been discharged VMGD (4 microns.

[0176] 在又一实施例中,用于输送可吸入干粉的系统包括:a)由FDKP晶体和药物构成的颗粒,其中FDKP异构体的比例在反式:顺式50%到65%的范围内;以及b)吸入器,包括粉末容纳封装、包括气体入口和气体出口的室;以及其中安装所述室并且限定两个流动通路的壳体,其中第一流动通路允许气体进入室的气体入口,第二流动通路允许气体绕过室的气体入口;其中绕过封装气体入口的气流被引导成撞击在与气体出口流动方向基本垂直的、从封装排出的气流上。 [0176] In yet another embodiment, the system, for the delivery of an inhalable dry powder comprising: a) particles composed of FDKP crystals and the drug, wherein the ratio of FDKP isomers in the trans: cis 50% to 65% the range; and b) an inhaler comprising a powder receiving chamber package comprising a gas inlet and a gas outlet; and wherein the mounting chamber and defining two flow paths of the housing, wherein the first flow path to allow gas to enter the gas chamber inlet, a second flow path allows the gas to bypass the chamber gas inlet; wherein the encapsulated gas bypass stream is directed into the inlet flow direction of impinging substantially perpendicular to the gas outlet, the gas stream discharged from the package.

[0177] 在某些实施例中,提供了用于输送可吸入干粉的系统,其包括:a)干粉,其包括由FDKP晶体和药物构成的颗粒,其中微粒具有在约35到约67m2/g之间的SSA,该微粒呈现出诸如改善的空气空力学性能和改善的药物吸附性等有益于向肺部输送药物的特性;b)吸入器,其包括粉末容纳封装,其中该封装包括气体入口和气体出口;以及安装室并且限定两个流动通路的壳体,第一流动通路允许气体进入室的气体入口,第二流动通路允许气体绕过室的气体入口;其中绕过室的气体入口的气流被引导成撞击在与气体出口流动方向基本垂直的、从封装排出的气流上。 [0177] In certain embodiments, a system for the delivery of inhalable dry powder, comprising: a) a dry powder comprising particles composed of FDKP crystals and the drug, wherein the particles have about 35 to about 67m2 / g SSA between the particles exhibit characteristics beneficial to delivery of drugs to the lungs such as improved mechanical properties and air space improved drug adsorption and the like; b) an inhaler comprising a powder receiving package, wherein the package comprises a gas inlet and a gas outlet; and a mounting chamber and the housing defining two flow paths, a first flow passage for admitting gas into the gas inlet chamber, a second flow path to allow gas to bypass the chamber gas inlet; a gas inlet chamber wherein the bypass impinging air flow is directed into the direction of the gas flow substantially perpendicular to the outlet, the gas stream discharged from the package.

[0178] 还提供了用于输送可吸入干粉的系统。 [0178] Also provided are systems for the delivery of an inhalable dry powder. 其包括:a)包括药物的干粉,以及b)吸入器,其包括粉末容纳药盒,其中药盒包括气体入口和气体出口;安装药盒并且限定两个流动通路的壳体,第一流动通路允许气体进入药盒的气体入口,第二流动通路允许气体绕过封装气体入口;嘴部及其上,其在吸入器上施加> 2kPa的压降,颗粒羽流从嘴部排出,其中50 %的被排出颗粒具有< 10微米的VMGD,其中绕过药盒的气体入口的气流被引导成撞击在与气体出口流动方向基本垂直的、从封装排出的气流上。 Comprising: a) a dry powder medicament, and b) an inhaler comprising a powder receiving cartridge, wherein the cartridge includes a gas inlet and a gas outlet; cartridge mounting housing and defining two flow pathways, a first flow path allowing gas to enter the gas inlet of the cartridge, a second flow passage allowing gas to bypass the gas inlet package; and the mouth portion, which applies> 2kPa pressure drop, the particle plume discharged from the nozzle portion in the inhaler, wherein 50% is discharged particles have a VMGD <10 microns, wherein the bypass flow inlet gas cartridge is guided to impact on the flow direction substantially perpendicular to the gas outlet, the gas stream discharged from the package.

[0179] 这里所述的合成物和方法中使用的活性剂可包括任何药用活性剂。 [0179] Here the active agent in the composition and method of use may comprise any pharmaceutically active agent. 这些可例如包括有机合成化合物,其包括具有治病、预防或诊断作用的血管扩张药、血管收缩分子、神经递质类似物、神经递质受体拮抗剂、类固醇、抗伤害性药物、肽和多肽、多糖和其他糖类、月旨类、无机化合物以及核酸分子。 These may include, for example, synthetic organic compounds, which include treatment, diagnosis or prevention vasodilator action, vasoconstriction molecules, neurotransmitters like, neurotransmitter receptor antagonists, steroids, anti-nociceptive drugs, peptides, and polypeptides, polysaccharides and other sugars, month purpose, inorganic compounds, and nucleic acid molecules. 肽、蛋白质和多肽都是通过肽键链接的氨基酸链。 Peptides, proteins and polypeptides are all chains of amino acids linked by peptide bonds.

[0180] 可利用二酮哌嗪制剂被输送到人体中的目标或位置的活性剂的示例包括激素、抗凝血剂、免疫调节剂、疫苗、细胞毒制剂、抗生素、血管活性药物、刺激神经组织的药物、麻醉剂或镇静剂、诸如包括氟替卡松、布地奈德、糠酸、环索奈德、氟尼缩松、倍他米松和曲安奈德的糖皮质激素等的类固醇、减充血剂、抗病毒药物、反义分子、抗原和抗体。 Example [0180] using a diketopiperazine formulation can be delivered to target the active agent in humans or position include hormones, anticoagulants, immunomodulating agents, vaccines, cytotoxic agents, antibiotics, vasoactive drugs, nerve stimulation tissue drugs, anesthetics or sedatives, such as including fluticasone, budesonide, mometasone, ciclesonide, flunisolide, betamethasone and triamcinolone acetonide glucocorticoids and other steroids, decongestants, anti-virus drugs, antisense molecules, antigens and antibodies. 更具体地,这些化合物包括胰岛素、肝素(包括低分子肝素)、降钙素、非氨酯、舒马曲坦、甲状旁腺激素及其活性成分、生长激素、促红细胞生成素、AZT、DDI、粒细胞巨噬细胞集落刺激因子(GM-CSF)、拉莫三嗪、绒毛膜促性腺激素释放因子、促黄体激素释放激素、β -半乳糖苷酶、醋酸艾塞那肽、血管活性肠肽、阿加曲班、包括抗肿瘤药物和抑制剂或包括抗伤害药物的诸如神经受体等细胞受体的类似物的小分子、包括琥珀酸舒马曲坦、阿莫曲坦曲坦苹果酸、利扎曲普坦苯甲酸、佐米曲普坦、依来曲普坦氢溴酸、那拉曲坦盐酸等的曲坦类药物、如沙丁胺醇非诺特罗福莫特罗特布他林吡布特罗、比托特罗、马来酸茚达特罗等的β 2-受体激动齐U、以及疫苗。 More specifically, these compounds include insulin, heparin (including low molecular weight heparin), calcitonin, felbamate, sumatriptan, parathyroid hormone and its active ingredient, growth hormone, erythropoietin, AZT, DDI , granulocyte macrophage colony stimulating factor (GM-CSF), lamotrigine, chorionic gonadotropin releasing factor, luteinizing releasing hormone, β - galactosidase, exendin, vasoactive intestinal peptide, argatroban, including anticancer drugs and include small molecule inhibitors or antinociceptive drugs such as nerve cell receptors receptor analogs, including sumatriptan succinate, almotriptan apple triptan acid, benzoic acid rizatriptan, zolmitriptan, eletriptan hydrobromide, naratriptan hydrochloride curved triptan drugs such as salbutamol terbutaline non 诺特罗福莫 Castro Lin pirbuterol, bitolterol, indacaterol maleate and the like receptor agonist β 2- homogeneous U, and vaccines. 抗体及其成分以非限制的方式可包括,反SSX-241_49 (滑膜肉瘤、X 断点2)、抗NY-ES0-1 (食管肿瘤相关抗原)、抗PRAME (黑色素瘤的优先表达抗原)、抗PSMA (前列腺特异性膜抗原)、抗Melan-A (黑色素瘤相关抗原)和抗酪氨酸酶(黑色素瘤相关抗原)。 Antibodies and ingredients may include a non-limiting manner, anti-SSX-241_49 (synovial sarcoma, X breakpoint 2), anti-NY-ES0-1 (esophageal tumor associated antigen), anti the PRAME (preferentially expressed antigen of melanoma) , anti-PSMA-(prostate specific membrane antigen), anti-Melan-A (melanoma associated antigen) and anti-tyrosinase (melanoma tumor associated antigen).

[0181] 在某些实施例中,用于向肺循环输送药物制剂的干粉制剂包括,活性成分或活性齐U,其包括肽、蛋白质、激素、及其类似物或其组合,其中活性成分是胰岛素、降钙素、生长激素、促红细胞生成素、粒细胞巨噬细胞集落刺激因子(GM-CSF)、绒毛膜促性腺激素释放因子、促黄体激素释放激素、卵泡刺激素(FSH)、血管活性肠肽、甲状旁腺激素(包括黑熊PTH)、甲状旁腺激素相关蛋白、胰高血糖素、胰高血糖素样肽-I (GLP-I)、醋酸艾塞那肽胃泌酸调节素、肽YY、白细胞介素2-诱导酪氨酸激酶、布鲁顿的酪氨酸激酶(BTK)、肌醇要求激酶I (IREl)、或类似物、活性成分、PC-DAC改性衍生物或其O-糖基化形式。 A dry powder formulation [0181] In certain embodiments, the pharmaceutical formulations for delivery to the pulmonary circulation comprises an active ingredient or active homogeneous U, which include peptides, proteins, hormones, and the like, or combinations thereof, wherein the active ingredient is insulin , calcitonin, growth hormone, erythropoietin, granulocyte macrophage colony stimulating factor (GM-CSF), chorionic gonadotropin releasing factor, luteinizing hormone releasing hormone, follicle stimulating hormone (FSH), vasoactive intestinal peptide, parathyroid hormone (including black bear of PTH), parathyroid hormone related protein, glucagon, glucagon-like peptide -I (GLP-I), exendin stomach oxyntomodulin, peptide YY, interleukin-2- induced tyrosine kinase, Bruton's tyrosine kinase (BTK), inositol kinase in claim I (IREl), or the like, the active ingredient, PC-DAC-modified derivatives, or O- glycosylated forms thereof. 在特定的实施例中,药物化合物或干粉制剂包括二酮哌嗪,并且活性成分是从以下各项中选取的一者:胰岛素、甲状旁腺激素1-34、61^-1、胃泌酸调节素、肽¥¥、肝素及其类似物;小分子,包括神经递质、衍生物和/或类似物或抑制剂/拮抗剂,诸如头痛调节器、头痛药物、偏头痛药物之类的抗伤害性药物,包括诸如曲坦类药物等的血管活性药物,疫苗及其佐剂;免疫抑制剂分子和抗癌药物。 In certain embodiments, a pharmaceutical formulation comprising a compound or a dry powder diketopiperazine and the active ingredient is selected from one of the following: insulin, parathyroid hormone 1-34,61 -1, gastric acid secretion somatomedins, ¥¥ peptide, heparin, and the like; small molecules, including neurotransmitters, derivative and / or analogue or inhibitor / antagonist, such as a regulator headache, headache drugs, anti-migraine drugs such nociceptive drugs, including drugs such as music and other triptan vasoactive drugs, vaccines and adjuvants; immunosuppressant and anticancer drug molecules.

[0182] 在一个实施例中,还提供了利用干粉吸入系统向患者的肺部自给予干粉制剂的方法。 [0182] In one embodiment, there is also provided a method of self-administering dry powder inhalation system using a dry powder formulations to the lungs of a patient. 该方法包括:获得在关闭位置并具有嘴部的干粉吸入器;获得在保持配置中包括预计量剂量的干粉制剂的药盒;打开干粉吸入器以安装药盒;关闭吸入器以实现药盒到给药位置的移动;将嘴部放入嘴中,以及一次深吸气以服用干粉制剂。 The method comprising: obtaining a closed position and in a dry powder inhaler having a mouth portion; obtaining a kit including the estimated amount of dosage dry powder formulation in the retention configuration; open a dry powder inhaler to install the cartridge; close to the inhaler to achieve kit moving the administering position; the mouthpiece into the mouth, and to take a deep breath dry powder formulations.

[0183] 在一个实施例中,通过了输送活性成分的方法,包括:a)提供包含药盒的干粉吸入器,药盒具有包括二酮哌嗪和活性成分的干粉制剂;以及b)将活性成分或活性剂输送给需要治疗的个体。 [0183] In one embodiment, the method of delivering the active ingredient, comprising: a) providing a kit comprising a dry powder inhaler, a dry powder formulation comprising a cartridge having a diketopiperazine and an active ingredient; and b) the active active ingredient or agent delivery to a subject in need of treatment. 干粉吸入系统可输送诸如具有大于50%的可吸入成分和尺寸小于 Dry powder inhalation system may be delivered such as a respirable composition and size of greater than 50% less than

5. 8 μ m的颗粒的胰岛素FDKP等的干粉制剂。 5. 8 μ m particles of the insulin FDKP dry powder formulation and the like.

[0184] 在又一实施例中,公开了治疗肥胖症、高血糖、胰岛素抵抗和/或糖尿病的方法。 [0184] In yet another embodiment, the disclosed treatment of obesity, hyperglycemia, insulin resistance and / or diabetes. 该方法包括服用包括二酮哌嗪的可吸入干粉合成物或制剂,二酮哌嗪具有2,5- 二酮-3,6-二次(4-X-氨基丁基)哌嗪的结构式,其中X是从由延胡索酰、琥珀酰、马来酰和戊二酰构成的组中选取的。 The method comprises administering diketopiperazine comprising inhalable dry powder composition or formulation, diketopiperazine having 2,5-diketo-3,6-secondary (4-X- aminobutyl) piperazine of the formula, wherein X is selected from the group consisting of fumaric acid, succinic acid, maleic acid, and the glutaryl. 在该实施例中,干粉合成物包括二酮哌嗪盐。 In this embodiment, the dry powder composition comprising a diketopiperazine salt. 在本发明的又一实施例中,提供了干粉合成物或制剂,其中二酮哌嗪是由或没有药学上可接受的盐或赋形剂的2,5- 二酮_3,6- 二次(4-延胡索酰-氨基丁基)哌嗪。 In yet another embodiment of the present invention, there is provided a dry powder composition or formulation, wherein the diketopiperazine is not or a pharmaceutically acceptable salt or excipient two 2,5-diketo _3,6- times (4 fumaric acid - aminobutyl) piperazine.

[0185] 在一个实施例中,用于向患者的肺部输送干粉制剂的吸入系统被配置成,在给药配置下具有从O. 065到约O. 200 ( V kPa)/liter每分钟范围的总流动阻力。 Inhalation system [0185] In one embodiment, a dry powder formulation for delivering to the lungs of a patient is arranged, having from about O. 065 O. 200 (V kPa) / liter per minute range at dosing configuration the total flow resistance.

[0186] 在一个实施例中,提供了包括干粉吸入工具包,其包括如上所述的吸入器和一个或多个药物药盒,药盒包括用于干粉制剂,干粉制剂用于治疗诸如呼吸道疾病、糖尿病和肥胖症等的失调或疾病。 [0186] In one embodiment, there is provided a kit comprising a dry powder inhaler comprising the inhaler described above and one or more pharmaceutical kit, the kit comprising a dry formulation, such as a dry powder formulation for the treatment of respiratory diseases , diabetes and obesity and other disorders or diseases. 在该实施例中,工具包可包括使用说明材料。 In this embodiment, a kit may include instructions for use material.

[0187] 这里所述的吸入系统的改进的药盒排空和解聚能力帮助增加干粉制剂的生物利用度。 [0187] an improved inhalation system described herein cartridge emptying disaggregation ability to help increase the bioavailability of the dry powder formulation. 在特定实施例中,干粉含有粉末的二酮哌嗪。 In a particular embodiment, dry powder-containing diketopiperazine. 生物利用度是指,如通常用浓度与时间曲线的AUC评价的、由向受试者的血液循环的输送产生的、对活性成分(例如胰岛素)或二酮哌嗪(在那些实施例中与二酮哌嗪粉末相关)的暴露量。 Bioavailability refers to, as commonly used concentration versus time AUC curve evaluation by the transport to the blood circulation of the subject produced, to the active ingredient (e.g. insulin) or diketopiperazine (in those embodiments with powder diketopiperazine-related) of exposure. 通过使这些测量对剂量进行归一化,可显示系统的特性。 By making these measurements for dose normalized characteristics of the system can be displayed. 在归一化暴露量时使用的剂量是基于所填充的剂量或被排出的剂量的,并且可以粉末的单位质量表示。 Dosages used in the exposure dose normalization is filled or discharged based on the dose, and may be expressed per unit mass of the powder. 或者,可以对药盒的特定填充量来归一化暴露量。 Alternatively, a kit may be specific filling amount of exposure to normalize. 以任何方式,可以进一步调节暴露量以考虑特定制剂的具体二酮哌嗪或活性成分的含量,即,可对在所填充剂量或被排出剂量中的活性成分的量或二酮哌嗪的量来归一化暴露量。 DETAILED diketopiperazine content in any manner, can be further adjusted to account for a particular exposure or formulation of the active ingredient, i.e., the amount or quantity of a diketopiperazine or discharging the dose of the active ingredient in the filled dose to normalize exposure. 与受试者有关的变量,例如液体量等会影响所观察到的暴露量,因此在各个实施例中,系统的生物利用度将以范围或界限表示。 The subject-related variables, for example, liquid amount of exposure will affect the observed, in various embodiments, therefore, the bioavailability of the system will be represented by ranges or limitations.

[0188] 在一个实施例中,粉末制剂可包括FDKP的微粒以及作为用于之类糖尿病的活性成分的胰岛素,其中制剂的胰岛素含量是每毫克粉末3U、4U、6U或更多。 [0188] In one embodiment, the powder formulation may comprise insulin and FDKP microparticles such as for diabetes active ingredient, wherein the content of insulin per mg of powder formulation 3U, 4U, 6U or more. 将被服用的胰岛素的量或剂量可根据患者的需要而变化。 The amount or dose of insulin to be administered can vary according to the needs of the patient. 例如,在一个实施例中,对于糖尿病中的高血糖的治疗,用于单次吸入的单次剂量可含有高达约60U胰岛素。 For example, in one embodiment, for the treatment of hyperglycemia in diabetes, the single dose for a single inhalation may contain up to about 60U insulin.

[0189] 胰岛素的药代动力学概况是确定生理影响时的重要因素。 [0189] The pharmacokinetic profile of insulin is an important factor in determining the physiological effects. 在类似的胰岛素暴露量的情况下,提供特征为较快达到峰值的制剂的胰岛素服用、比导致较慢地上升到Cmax并且以延长的高值为特征的胰岛素服用、在抑制餐后血糖偏移和肝葡萄糖释放方面更有效。 In the case of similar insulin exposure, providing faster peak characterized by insulin formulation administration, Cmax ratio rises to result in slower and prolonged insulin taking high value feature, the shift suppressing postprandial hyperglycemia hepatic glucose release and more effective. 因此,这里所公开的吸入系统还产生更有效的胰岛素输送,从而与现有技术的系统相比,能够以较小的胰岛素剂量得到相似的Cmax水平。 Accordingly, the intake system disclosed herein also result in more efficient delivery of insulin, as compared with prior art systems, a small dose of insulin can be obtained a similar Cmax level. 除了记录的、否则这些吸入系统得到较高的剂量归一化的Cniax。 In addition to recording, otherwise these intake system get a higher dose normalized Cniax.

[0190] 示例I [0190] Example I

[0191] 测量干粉吸入器-药盒系统的阻力和流量分布 [0191] Measurement dry powder inhaler - cartridge system and the flow resistance distribution

[0192] 测试了一些干粉吸入器设计以测量它们的流动阻力,流动阻力是部分由吸入器通路的几何形状或配置所确定的重要特性。 [0192] Some were tested dry powder inhaler designed to measure their flow resistance, the flow resistance is an important characteristic of the geometry or configuration of portions of the pathway by the inhaler determined. 显示出较高阻力的吸入器需要更高的压降以产生与较低阻力的吸入器相同的流速。 Exhibit high resistance inhaler requires a higher pressure drop to produce a low resistance inhaler same flow rate. 简要地说,为了测量各个吸入器和药盒系统的阻力,对吸入器施加各种流速并且测量所产生的在吸入器上的压力。 Briefly, in order to measure the resistance of each inhaler and cartridge system, various flow rates is applied to the inhaler and measuring the resulting pressure on the inhaler. 这些测量可以使用连接到吸入器的嘴部的真空泵来提供压降、并且使用流量控制器和压力计来改变流量和记录所产生的压力。 These measurements may be used a vacuum pump connected to the nozzle portion of the inhaler to provide a pressure drop, and a pressure gauge and a flow controller used to vary the flow rate and the pressure generated by the recording. 根据伯努利原理,当相对于流速来绘制压降的平方根时,吸入器的阻力是曲线的线性部分的斜率。 According to the Bernoulli principle, when the velocity plotted with respect to the square root of the pressure drop, resistance of the inhaler is the slope of the linear portion of the curve. 在这些实验中,利用阻力测量设备测量了在给药配置下的、如本文所述的包括干粉吸入器和药盒的吸入系统的阻力。 In these experiments, using a resistance measuring device to measure the resistance in the dosing configuration, such as a dry powder inhaler comprising the inhaler and cartridge system as described herein. 给药配置形成通过吸入器空气管道并通过在吸入器中的药盒的空气通路。 Administration through the inhaler configuration is formed by an air duct and a cartridge in the inhaler in an air passage.

[0193] 因为不同的吸入器设计由于在其空气通路的几何形状上的轻微改变而显示出不同的阻力,所以进行了多个实验,以确定使用特定设计时的压力设置的理想间隔。 [0193] Since different inhaler designs due to a slight change in its air passageway geometry exhibits different resistance, so that a plurality of experiments conducted to determine the ideal interval pressure when the particular design settings. 基于压力的平方根和流速之间的线性关系的伯努利原理,在多个测试之后对所使用的三个吸入器预定了用于估算线性关系的间隔,以使得适合的设置可用于其他批次的相同吸入器设计。 Based on the Bernoulli principle of linearity between square root of pressure and flow rate, after a plurality of tests on three inhalers used for estimating a predetermined interval in a linear relationship, so that the appropriate settings can be used for other batches the design of the same inhaler. 从图33中可以看到图7所示的吸入系统的吸入器的示例图。 Inhaler can be seen in the example of FIG 7 the suction system shown in FIG. 33 from FIG. 图33所示的曲线图表明,如图7所示的吸入系统可以在从约10到约25L/min的流速范围内、在与伯努利原理良好相关的情况下进行测量。 Graph shown in FIG. 33 indicate that inhalation system shown in Figure 7 can be measured in good correlation to the Bernoulli principle is within the range from about 10 to about 25L / min flow rate range. 曲线还示出了示例性吸入系统的阻力被确定为O. 093 VkPa/LPM。 Resistance curve also shows an exemplary inhalation system was determined to be O. 093 VkPa / LPM. 图33图示出流速和压力是相关的。 FIG 33 illustrates a flow and pressure are related. 因此,随着压力的平方根与流速图中的直线的斜率减小,即随着吸入系统显示出较低的阻力,对于给定的压力变化,流速的变化较大。 Accordingly, as the slope of the square root of the flow rate in view of the pressure line is reduced, i.e. as suction systems show a lower resistance for a given pressure change, large changes in flow rate. 因此,较高阻力的吸入系统对于由患者利用呼吸功能系统所提供的给定的压力变化,将显示出较小的流速变化。 Accordingly, higher resistance inhalation system for a given change in pressure provided by the patient using a respiratory system, will show less change in flow rate.

[0194] 表I中的数据示出了利用图10所示的(DPI I)和图7所示的(DPI2)吸入系统的一组实验的结果。 [0194] Data in Table I shows the results of using the FIG (the DPI I) and a set of experiments intake system shown in (DPI2) 10 shown in FIG. 7. 对于干粉吸入器UDPI 1),使用了图17-21、设计150中所示的药盒,并且DPI 2使用了图22-30、设计170中所示的药盒。 For dry powder inhaler UDPI 1), 17-21 using a design as shown in the kit 150, and DPI 2 used in FIG. 22-30, the kit 170 illustrated design. 因此,DPI I使用药盒I并且DPI使用药盒2。 Thus, the use of the kit I I DPI and DPI 2 used cartridge.

[0195]表 1 [0195] TABLE 1

[0196] [0196]

Figure CN102985125AD00331

[0197] 表I图示了这里所测试的吸入系统的阻力,对于DPI I和DPI 2分别是0.0874和O. 0894 V kPa/LPM。 [0197] Table I illustrates the resistance of the inhalation system tested here, for the DPI and DPI 2 I are 0.0874 and O. 0894 V kPa / LPM. 该数据示出了吸入系统的流动阻力部分地由药盒内的空气管道的几何形状或配置决定。 This data shows the intake system determined in part by the flow resistance in the air duct kit geometry or configuration.

[0198] 示例2 [0198] Example 2

[0199] 使用具有胰岛素制剂的吸入系统的粒径分布的测量 Measurement [0199] with the use of insulin preparations inhalation system particle size distribution

[0200] 对设置在如本文所述的药盒-吸入器系统(图1-9的吸入器和图22-30所示的药盒170)中的胰岛素和延胡索酰二酮哌嗪颗粒的各种量(mg)的制剂,利用具有适配器(Mannkind公司,美国专利申请No. 12/727,179,对于相关主题的教导,该申请的公开通过引用结合于此)的激光衍射设备(HEL0S激光衍射系统,新帕泰克公司),进行了粒径分布的测量。 [0200] As provided herein for the kit - each (FIGS. 1-9 cartridge and the inhaler 170 shown in FIG. 22-30) insulin inhaler system and fumaric acid diketopiperazine particles formulation species amount (mg), the use of a laser diffraction apparatus (HEL0S adapter having laser diffraction (Mannkind Corporation, U.S. Patent application No. 12 / 727,179, the teachings of related topics, the disclosure of which is hereby incorporated herein by reference) in system, Sympatec), were measured particle size distribution. 将设备在一端连接到适用于流量计(TSI公司,型号4043)的管子和用于调节来自压缩空气源的压力或流速的阀。 The device is connected at one end to a suitable flow meter (TSI, model 4043) and a pipe for regulating pressure or flow rate of the valve from the compressed air source. 当激活激光系统并且激光束准备好测量羽流时,驱动气动阀以允许粉末被从吸入器排出。 When the laser system is activated and the laser beam is ready to measure a plume, a pneumatic valve to allow the drive to be discharged from the powder inhaler. 激光系统基于预定的测量条件自动地测量从吸入设备排出的羽流。 The laser system of automatically measuring the plume exiting the inhaler device based on predetermined measurement conditions. 激光衍射系统通过与设备集成的软件来操作,并且由计算机程序来控制。 Laser diffraction system is operated by software integrated with the device, and are controlled by a computer program. 对包含不同粉末量和不同的粉末堆的样本进行了测量。 Samples containing different amounts of powder and different powder bulk was measured. 测量条件如下: Measurement conditions are as follows:

[0201] 激光测量开始触发条件:当在特定的检测器通道检测到> O. 6%的激光强度时; [0201] Laser measurement start trigger conditions: when it is detected> O. 6% of the laser intensity at a particular detector channel;

[0202] 激光测量结束触发条件:当在特定的检测器通道检测到< O. 4%的激光强度时;[0203] 真空源和吸入室之间的距离约为9. 525cm。 [0202] Laser measurement end trigger conditions: when detecting <O. 4% of the laser intensity at a particular detector channel; [0203] The distance between the vacuum source and the suction chamber is about 9. 525cm.

[0204] 使用在药盒中的不同的粉末量或填充量进行了多次测量。 [0204] use in the kit of different powder filling amount or amount of multiple measurements. 药盒仅使用一次。 The kit is used only once. 在粉末从吸入器排出之前和之后确定药盒重量,以确定所排出的粉末重量。 Before the powder is discharged from the inhaler and cartridge after determining the weight to determine the weight of the powder discharged. 如下面的表2所示,在各种压降下并重复多次地确定在设备中的测量。 As shown in Table 2 below, and repeated several times to determine a measurement in the device under various pressure drops. 测量了粉末羽流之后,对数据进行分析并且绘图。 After the powder plume is measured, the data were analyzed and plotted. 图2描述了从实验得到的数据,其中CT表示药盒空出(粉末被排出)并且Q3 (50% )表示样本的累积粉末粒径分布第50个百分点的几何直径,q3 (5. 8 μ m)表示几何直径小于5. 8 μ m的粒径分布的百分比。 Figure 2 depicts data obtained from experiments wherein CT represents an empty cartridge (powder discharged) and Q3 (50%) represents the cumulative geometric diameter of the powder particle size distribution of samples of the 50th percentile, q3 (5. 8 μ m) represents the particle geometric diameter is less than the percentage of 5. 8 μ m distribution.

[0205] 表2中的数据表明,粉末填充总量的92. 9%至98. 4%被从吸入系统排出。 [0205] The data in Table 2 show that 92.9 to 98.4% of the total amount of the powder filling is discharged from the inhalation system. 此外,该数据表明,如在各种时间和压降下所测量的,无论填充量如何,从吸入系统排出的颗粒的50%具有小于4.7μπι的几何直径。 In addition, the data show that, as in the various times and the measured pressure drop, regardless of the filling amount, having a geometric diameter of less than 50% 4.7μπι inhalation system from discharging particles. 而且,被排出的颗粒的60 %和70 %之间具有小于5. 8 μ m的几何直径。 Further, having a geometric diameter of less than 5. 8 μ m of between 60% and 70% of the particles are discharged.

[0206] 图34描述了从使用IOmg的填充量的另一个实验所得到的数据。 [0206] FIG 34 depicts data from another experiment using the filling amount of the obtained IOmg. 曲线示出了含有包括胰岛素和延胡索酰二酮哌嗪(FDKP)颗粒的制剂的样本的粒径分布,该分布的结果为78. 5%的被测量颗粒具有< 5. 8 μ m的颗粒尺寸。 Curve shows that the sample containing formulations comprising insulin and a diketopiperazine fumaric acid (the FDKP) particle size distribution, the results of the distribution of 78.5% of the particles have a particle size is measured <5. 8 μ m of . 在上述测量条件下,激光在O. 484秒的测量持续时间期间,检测了37. 67%的光学浓度。 Under the measurement condition, the laser O. 484 seconds during the measurement duration, detecting the optical density of 37.67%. 该数据示出,吸入系统在用户吸入容量(即压降)的相关和较低范围内有效地将胰岛素-FDKP制剂解聚为较小尺寸。 The data shows that, in the inhalation system user capacity suction (i.e., pressure drop) is related to a lower range and effectively -FDKP insulin formulation depolymerization smaller size. 对于该粘性(卡尔指数=36% )来说这些较小几何尺寸被认为是可吸入的。 For the adhesive (Carr index = 36%) for these smaller geometric dimensions it is considered respirable.

[0207]表 2 [0207] TABLE 2

[0208] [0208]

Figure CN102985125AD00341

[0209]不例 3 [0209] Example 3 is not

[0210] 作为吸入系统的性能测量的粉末从药盒排出的测量 [0210] As the suction performance measurement system measuring the powder discharged from the cartridge

[0211] 利用本文所描述的吸入系统进行了实验,该吸入系统使用图1-9所述的多个吸入器原型和图22-30所述的药盒170原型。 [0211] using the inhalation system described herein experiments were carried out using the suction system of FIG. 1-9 and FIG plurality inhaler cartridge 170 prototypes Prototype 22-30. 每个吸入器使用多个药盒。 Each of the plurality of inhaler cartridge. 每个药盒在填充前在电子天平上称重。 Each cartridge was weighed on an electronic balance prior to fill. 将药盒填充预定量的粉末,再次称重,并且将每个已填充的药盒放入吸入器并且对其排空粉末制剂即lT:CHNOSPHF:RF:f胰岛素(胰岛素-FDKP ;通常每毫克粉末含3U-4U胰岛素,约10-15%胰岛素w/w)粉末批次的效率进行测试。 Filling a predetermined amount of the powder cartridge, again weighed and each filled cartridge into the inhaler and emptying a powder formulation thereof i.e. lT: CHNOSPHF: RF: f Insulin (insulin-FDKP; typically per milligram 3U-4U containing powder insulin, insulin efficiency of about 10-15% w / w) powder batches were tested. 使用多个压降以描绘性能的连贯性特性。 A plurality of voltage drop to delineate coherent performance characteristics. 图3描述了每个吸入器使用35药盒排放测试的该测试的结果。 Figure 3 depicts the results of each inhaler 35 use the test kit emissions test. 在表3的数据中,所有的测试都是使用相同批次的临床级胰岛素-FDKP粉末。 Data in Table 3, all the tests were using the same lot of clinical grade insulin -FDKP powder. 该结果示出,从2至5kPa范围的相关用户压降展示了粉末从药盒高效地排空。 This result shows that the range from the user related to 5kPa 2 shows a pressure drop effectively evacuated from the powder cartridge.

[0212]表 3 [0212] TABLE 3

[0213] [0213]

Figure CN102985125AD00351

[0214] 示例4 [0214] Example 4

[0215] 通过安德森阶式嵌塞的预测沉积的测量 [0215] predicted by Anderson cascade impaction measurements deposited

[0216] 通过在利用28. 3LPM流速的模拟剂量的给药期间、利用安德森阶式嵌塞来收集台阶板粉末沉积物来进行实验。 [0216] Experiments were performed by using an analog dose during the dosing flow rate of 28. 3LPM by Anderson cascade impaction plate to collect powder deposits step. 28. 3LPM的流速在吸入系统(DPI+药盒)上产生大约6kPa的压降。 28. 3LPM flow rate of pressure drop at about 6kPa inhalation system (DPI + cartridge) on. 利用过滤器和电子天平在重量上分析在台阶板上的沉积物。 Analysis of deposits on the step plate and the filter weight using an electronic balance. 对于吸入器的性能,分别评估了10mg、6. 6mg和3. Img填充量的粘性粉末。 For the performance of the inhaler, we were evaluated 10mg, 6. 6mg 3. Img and the filling amount of cohesive powders. 每次嵌塞利用5个药盒来进行。 Using each caulking cartridge to 5. 根据小于5. 8 μ m的空气动力学粒径测量了在台阶2-F上收集的积累粉末量。 The aerodynamic diameter of less than 5. 8 μ m air measured amount of powder collected on the accumulation of the step 2-F. 积累的粉末量相对于药盒填充物的比例被确定,并且被提供为相对于填充重量的可吸入部分(RF)的百分比。 The accumulated amount of the powder cartridge with respect to the proportion of the filler is determined, and is provided as a suction part (RF) relative to the fill weight percentage. 数据见表4。 Data in Table 4.

[0217] 该数据示出,对于多个粉末批次,实现了从50%到70%范围的可吸入比例。 [0217] The data shows that for a plurality of batches of powder, achieve a ratio of respirable range from 50% to 70%. 该范围表示吸入系统的归一化性能特性。 This range represents a normalized intake system performance characteristics.

[0218] 利用不同的药盒重复了35次吸入系统性能测量。 Different [0218] 35 was repeated using the kit inhalation system performance measurements. 对所使用的每个吸入器药盒系统测量了填充量(mg)和排放时间(S)。 For each inhaler cartridge system used was measured filling amount (mg) and discharge time (S). 此外,还测量了可吸入含量的百分比,即,粉末中的适合于肺部给药的颗粒。 In addition, measuring the percentage of respirable content, i.e., particles suitable for pulmonary administration powder. 结果见下面的表4。 The results are shown below in Table 4. 在表中,%RF/fill等于粉末中的、将要进入肺部的具有尺寸彡5. 8 μ m的颗粒的百分比;CE表示药盒空出或粉末已输送;RF表示可吸入部分。 In the table,% RF / fill equals the percentage μ m particles in the powder will have a size to enter the lungs San 5. 8; CE indicates cartridge emptying or powder has been delivered; respirable represents the RF section. 在表4中,利用第二批次的临床级胰岛素-FDKP粉末进行测试序号1-10,测试序号 In Table 4, the second batch using clinical-grade powder insulin -FDKP test ID 1-10, test ID

11-17的测试粉末使用与在表3中进行和展示的测试相同的粉末。 11-17 Test powder powder using the same testing performed and is shown in Table 3.

[0219]表 4 [0219] TABLE 4

[0220] [0220]

Figure CN102985125AD00361
Figure CN102985125AD00371

[0222] 上面的数据表明,包括干粉吸入器和装有粘性粉末即,TECHNOSPHERE®,胰岛素(包含胰岛素的FDKP颗粒)的药盒的该吸入系统,可以有效地排出几乎所有的粉末容纳物,这是因为其在连贯性和显著排空的情况下得到了在各种填充量和压降下、大于总药盒容纳物的85%和在大多数情况下大于95%的结果。 [0222] The above data show that, and a dry powder inhaler comprising a powder containing viscous i.e., TECHNOSPHERE®, Insulin (FDKP particles comprising insulin) a kit of the suction system, can be efficiently discharged almost all of the powder contents, which is because it was in the case of coherent and significantly emptying and filling amount in each drop, and the results of more than 85% greater than 95% of the total, in most cases the kit contents. 安德森阶式碰撞取样测量表明,多于50%的颗粒落在小于5. 8 μ m并且从总排放粉末的53. 5%至73%的可吸入范围中。 Anderson Cascade Impactor measurements indicated that more than 50% of the particles fall and less than 5. 8 μ m 53.5 to 73% of total emissions from the powder in the respirable range.

[0223]示例 5 [0223] Example 5

[0224] TECHNOSPHERE_夷岛素(Tl)的皱褶状态 [0224] TECHNOSPHERE_ Yi Insulin (Tl) folds state

[0225] 皱褶状态是相对于等效球体比表面积、粒子的实际比表面积。 [0225] wrinkles state equivalent spherical surface area with respect to the actual specific surface area of ​​the particles. 球体的比表面积是: The specific surface area of ​​a sphere is:

Figure CN102985125AD00372

[0226] 其中,deff = I. 2 μ m是根据Sympatec/RODOS激光衍射测量的TI颗粒的表面加权直径。 [0226] wherein, deff = I. 2 μ m is the surface-weighted diameter of the TI particles Sympatec / RODOS laser diffraction measurements. FIG.

[0227] 因此,与TI颗粒基质的密度(I. 4g/cm3)相同的一般球体将具有如下SSA : [0227] Thus, the density (I. 4g / cm3) TI particulate substrate having the same general sphere follows SSA:

[0228] [0228]

Figure CN102985125AD00373

[0229] 因此,对于具有约40m2/g比表面积(SSA)的TI颗粒, [0229] Thus, for about 40m2 / g specific surface area (SSA) of the TI particles,

[0230] [0230]

Figure CN102985125AD00381

[0231] 对于具有50或60的比表面积的相似尺寸的颗粒,皱褶状态分别大约是14和16。 [0231] 14 and 16, respectively, for approximately similar dimensions having a specific surface area of ​​particles of 50 or 60, the state of wrinkles.

[0232] 示例6 [0232] Example 6

[0233] 通过体积中值几何直径(VMGD)表征的被排出制剂的几何粒径分析 [0233] By volume median geometric diameter (a VMGD) Characterization Analysis geometric diameter is discharged formulation

[0234] 从干粉吸入器排出的干粉制剂的激光衍射是表征粉末所经受的解聚的水平所采用的一般方法。 [0234] General procedure depolymerization level of powder subjected employed from laser diffraction dry powder formulation is a dry powder inhaler discharge characterization. 该方法表示了作为在工业标准嵌塞方法中发生的几何尺寸而不是空气动力学粒径的测量。 This method represents a geometry occurring in industry standard impaction method instead of the aerodynamic particle size was measured. 通常,被排出粉末的几何尺寸包括由中值粒径所表征的体积分布(VMGD)。 Typically, the powder is discharged geometry comprises a volume distribution (a VMGD) characterized by the median particle diameter. 重要的是,相对于有嵌塞方法提供的空气动力学粒径,被排出颗粒的几何尺寸被用提高的分辨率识别出。 Importantly, with respect to the aerodynamic particle size caulking method has provided the geometry of the particles discharged are identified with improved resolution. 较小的尺寸是优选的,并且其产生单个粒子被输送到肺呼吸道的较大的可能性。 Smaller size is preferred, and it is a greater likelihood of individual particles being delivered to the airways of the lungs. 因此,利用衍射可以更容易地解决吸入器解聚和最终性能的差异。 Thus, the use of diffraction can be more easily resolve differences inhaler depolymerization and final properties. 在这些实验中,利用激光衍射、在与实际患者吸气容量类似的压力下、测试了如示例3所指出的吸入器和可能的吸入器,以确定吸入系统的解聚粉末制剂的效率。 In these experiments, by laser diffraction, in the actual patient inspiratory capacities similar pressures, were tested as indicated in the example and may inhaler inhaler 3, the intake system to determine the efficiency of the depolymerization powder formulation. 具体而言,所述制剂包括具有和不具有活性胰岛素添加成分的粘性二酮哌嗪粉末。 Specifically, the formulation comprises an adhesive diketopiperazine powders with and without the added components of the activity of insulin. 这些粉末制剂具有比表面积、同素异构体比例和卡尔指数。 The powder formulation has a specific surface area, and allotropic body ratio Carr index. 表5中所报告的是VMGD以及在测试期间容器排空的效率。 Table 5 are reported VMGD and emptying of the container during testing efficiency. FDKP具有约50的卡尔指数,并且TI粉末具有约40的卡尔指数。 FDKP having a Carr index of about 50, and a powder having a Carr index TI of about 40.

[0235] 表5中的这些数据表明,本文所描述的吸入器系统比可能的吸入器改善了粉末解聚。 The data [0235] Table 5 shows that the inhaler system described herein improves powder than is possible depolymerization inhaler. 表面积从14至56m2/g范围的二酮哌嗪粉末展示出超过85%的排空效率以及小于7微米的VM⑶。 A surface area from 14 to 56m2 / g diketopiperazine powders exhibit a range of more than 85% efficiency, and emptying VM⑶ less than 7 microns. 类似地,具有从45%至66% trans的同素异构体比例的制剂,展示出比可能的设备改善了性能。 Similarly, a formulation from a body allotropic ratio 45% to 66% trans, demonstrating the improved performance of the device than is possible. 最后,示出了具有卡尔指数40-50的特性的制剂的吸入系统的性能,也比可能的设备得到了改善。 Finally, the system shows the performance of the inhalation formulation has a characteristic Carr index 40-50, the ratio may be also improved device. 在所有情况下,所记录的VMGD值都小于7微米。 In all cases, VMGD recorded values ​​are less than 7 microns.

[0236]表 5 [0236] TABLE 5

[0237] [0237]

Figure CN102985125AD00391

[0239]示例 7 [0239] Example 7

[0240] 在下一代干粉输送系统中实现的体外性能改善 [0240] In vitro performance achieved in the next generation to improve the dry powder delivery system

[0241 ] TECHNOSPHERE⑩制剂已经利用MEDT0NE⑩输送系统(MTDS,MannKind公司,瓦伦西亚,CA)成功地输送给患者。 [0241] TECHNOSPHERE⑩ formulations have been utilized MEDT0NE⑩ delivery system (MTDS, MannKind Corporation, Valencia, CA) successfully delivered to the patient. 该系统包括干粉制剂、预计量的一次性药盒以及插入在高阻抗中、呼吸功能的、可重复使用的MEDTONE⑩吸入器。 The system comprises a dry powder formulation, premetered disposable inhaler cartridge is inserted and MEDTONE⑩ high impedance, the respiratory function, reusable. 已经开发了作为MTDS的替代物的改进的输送系统(如示例I所述的DPI 2)。 Have been developed as an alternative to the MTDS improved delivery systems (such as the exemplary DPI I 2). 针对吸入器性能的各种参数,比较了这些系统的体外粉末性能。 For various performance parameters of the inhaler, the powder was compared in vitro performance of these systems. 对于DPI 2,使用了每个药盒一个排放口与在MEDTONEf)系统中的每个药盒两个排放口比较。 For DPI 2, using a discharge port of each cartridge is compared with each of the two discharge ports in the cartridge MEDTONEf) system.

[0242] 在这些实验中使用了如上所述的通过激光衍射进行的粒径测量和被排出质量的量化。 [0242] By using a laser diffraction particle size measuring and discharged as described above, quantized quality in these experiments. 采用了带有新型加压吸入器室的激光衍射仪器(Sympatec HEL0S)以便于分析粉末羽流。 Using a laser diffraction instrument with a new type of inhaler pressurized chamber (Sympatec HEL0S) to facilitate analysis of the powder plume. 每次判定MEDS药盒排放两次而DPI 2排放一次。 Each cartridge is determined MEDS discharged twice and once DPI 2 emissions. 以4kPa的峰值压力使用吸入系统,以利用TECHNOSPHERE® (FDKP 吸入粉末)和TECHNOSPHERE®胰岛素(FDKP-胰岛素吸入粉末)制剂来评估粉末排空百分比和体积中值几何尺寸(VMGD)。 A peak pressure of 4kPa inhalation system used, to utilize TECHNOSPHERE® (FDKP inhalation powder) and TECHNOSPHERE® insulin (FDKP-insulin inhalation powder) formulations evaluation value and the volume percentage of powder emptying geometry (VMGD). ·[0243] 实验的结果如表6和图35所示。 * [0243] The results of the experiment are shown in Table 6 and FIG. 35. 总的来说,对于DPI 2,粉末排空百分比是97. 8%(FDKP-胰岛素,填充重量3. 5mg ;n = 20) ,96.8% (FDKP-胰岛素,填充重量6. 7mg ;n = 20)和92.6% (FDKP吸入粉末,填充重量10. Omg ;n = 15) ;VMGD (微米)分别是4. 37,3. 69和6.84。 In general, for DPI 2, evacuated powders percentages 97. 8% (FDKP- insulin, fill weight 3. 5mg; n = 20), 96.8% (FDKP- insulin, fill weight 6. 7mg; n = 20 ) and 92.6% (FDKP inhalation powder, fill weight 10. Omg; n = 15); VMGD ([mu] m) were 69 and 37,3 4. 6.84. 对于MTDS,粉末排空百分比是89. 9% (FDKP-胰岛素,填充重量5. Omg ;n = 30),91. 7% (FDKP-胰岛素,填充重量10. Omg ;n = 30)和89. 4 % (FDKP吸入粉末,填充重量10. Omg ;n = 30)。 For MTDS, powder emptying percentage was 89. 9% (FDKP- insulin, fill weight 5. Omg; n = 30), 91 7% (FDKP- insulin, fill weight 10. Omg; n = 30). And 89. 4% (FDKP inhalation powder, fill weight 10. Omg; n = 30). VMGD (微米)分别是10. 56、11. 23 和21. 21。 A VMGD ([mu] m) 10. 56,11 respectively 23 and 21.21.

[0244] 图35图示了根据对每个吸入系统进行的所有测试的平均值得到的数据的图形表示。 [0244] FIG. 35 illustrates a graphical representation of the average of all tests for each of the intake system of the data obtained. 从图35中可以看出,DPI 2的粒径累积分布小于ML.DTONLXR:的粒径累积分布。 As it can be seen from FIG. 35, DPI particle size cumulative distribution is less than 2 ML.DTONLXR: cumulative particle diameter distribution. 当与MEDT0NE®,相比时,DPI 2吸入系统呈现出具有较大百分比的较小颗粒。 When the MEDT0NE®, when compared, DPI 2 exhibits a suction system having a larger percentage of the smaller particles. 这证明在DPI2系统中改善了解聚机制。 This proves improve depolymerization mechanism DPI2 system. 这些数据支持DPI 2作为用于输送FDKP吸入粉末制剂的可行的并且改进的替代物的临床使用。 These data support the clinical use of DPI 2 inhalation powder formulation as feasible for conveying FDKP and improved alternatives. DPI 2的排空百分比被提高,相对于两个排放口的MTDS提供给用户每个药盒一个排放口的显著优势。 2 DPI emptying percentage is increased, the user provides a significant advantage to a discharge port of each of the cartridge with respect to the discharge opening of two MTDS. 中间几何粒径的减少暗示了在DPI 2中粉末解聚的增加。 Reduce intermediate geometric diameter it implies increased DPI 2 powder depolymerization. 现在必须评价这种增加的解聚的临床影响。 The clinical impact of this increased depolymerization must now be evaluated.

[0245]表 6 [0245] TABLE 6

[0246] [0246]

Figure CN102985125AD00411

[0247]示例 8 [0247] Example 8

[0248] 利用吸入系统的示例性实施例的FDKP的生物利用度的提高 FDKP enhance bioavailability of the exemplary embodiments [0248] With the intake system

[0249] 为了评估由DPI I (如上示例I所述)输送的各种填充重量的Till INOSPHERtP及入粉末(FDKP-吸入粉末)的安全性和容忍度,利用吸入系统(即,吸入器和装有各种填充重量的吸入干粉)、修改的CQLQ、VAS和吸入系统的峰值流量进行了测试。 [0249] In order to evaluate the various Till INOSPHERtP fill weight delivered by the DPI I (as the Example I) and the powder (FDKP-inhalable powders) the safety and tolerance, using a suction system (i.e., the inhaler and containing various inhalable dry powder fill weight), the modified peak flow CQLQ, VAS, and inhalation system tested. MEDTONE®吸入系统用来做比较。 MEDTONE® inhalation system used for comparison. 为了评估改变吸入作用力和吸入次数对通过DPI I吸入器作为FDKP-吸入器粉末被吸入的FDKP的药代动力学的影响,还进行了实验以从使用的系统收集数据。 To assess the frequency change and the suction force of the suction through the inhaler DPI I as FDKP- affect the pharmacokinetics of inhaled powder inhaler FDKP also conducted experiments to be used to collect data from the system.

[0250] 在研究的开始,受试者被指导并指示利用结合了如在美国专利申请No. 12/488, 469中所公开的压力传感装置的吸入系统进行“短”吸入和“长”吸入,其中所述压力传感装置可以检测从使用中的设备排出的剂量的存在。 [0250] the start of the study, subjects were instructed to use and combined as indicated in U.S. Patent Application No. 12/488, intake system pressure sensing device 469 disclosed a "short" and suction "long" inhalation, wherein said pressure sensing means can detect the presence discharged from the apparatus in use dose. 在吸入演习期间,受试者被指示结合3-4秒的短吸入或6-7秒的长吸入,维持4-6kPa的名义上的压力差。 During inhalation maneuvers, the subject is instructed to bind short or long suction intake of 3-4 seconds 6-7 seconds, to maintain the pressure difference between nominal 4-6kPa. 为了产生“困难”的吸入,受试者提供约6. 5秒的名义吸入时间和7kPa的峰值压力。 To generate the suction, "difficult", the name of the subject for about 6.5 seconds to provide a suction peak pressure and time of 7kPa. 相反,为了产生“容易”吸入,受试者提供约6. 5秒的名义吸入时间和5kPa的峰值压力。 Conversely, in order to produce "easy" inhalation, providing the name of the subject for about 6.5 seconds of inhalation time and peak pressure 5kPa. 结合吸入监测装置,进行了从药盒排出的粉末量的重量评估。 Means monitoring inhalation binding, were assessed by weight of the amount of powder discharged from the cartridge. 这使得每个受试者的在给药期间的吸入演习、药盒排放量和药动学特征测定之间相链接。 This enables the inhalation maneuver for each subject during administration, kits linked between emissions and pharmacokinetic profile measured.

[0251] 该研究是在健康志愿者中的开放性试验、交叉的、分为两部分的研究。 [0251] The study was an open trial in healthy volunteers, the cross is divided into two-part study. 在部分I中,进行了10的三路、三期交叉研究,并且通过DPI I吸入器吸入15mg的FDKP吸入粉末,并且通过MEDTONE®吸入器吸入IOmg的FDKP吸入粉末。 In Part I, 10 were three-way, three crossover study, and by the DPI inhaler I to FDKP inhalation powder 15mg and the FDKP inhalation powder by inhalation IOmg MEDTONE® inhaler. 十个被试者服用了一剂FDKP吸入粉末并且进行了安全性和容忍性测量(CQLQ、VAS和峰值流量)。 Ten subjects taking a FDKP inhalation powder was conducted and the safety and tolerance of measurement (CQLQ, VAS, and peak flow). 在服药之前以及在服药后的5、10、15、25、30、60、120、240和360分钟以后抽取受试者的血样,评估每种疗法的FDPK的药代动力学。 Blood samples were taken before dosing and at 5,10,15,25,30,60,120,240 subject and after 360 minutes after dosing, each treatment evaluation FDPK pharmacokinetics.

[0252] 在部分2中,在部分I中确定了FDKP吸入器粉末的容忍性以后,然后在部分2中使用10mg。 [0252] In Part 2, Part I determined in the tolerance FDKP powder inhaler after use and 10mg in 2 portions. 部分2以两部分、两路交叉研究进行,以评估流速(15LPM与30LPM相比)和吸入时间(3秒和6秒相比)的影响。 Part 2 in two parts, two-way crossover study was conducted to assess the impact velocity (compared to 15 LPM and 30 LPM) and inhalation time (3 seconds and 6 seconds compared to) a. 对于所测试的每个参数(即,流速和吸入时间),对于每个参数交叉10个受试者,并且对于所有参数共有20个受试者。 For each parameter tested (i.e. flow rate and inhalation time), for each parameter intersection 10 subjects, and a total of 20 parameters for all subjects. 对每种疗法、根据从受试者抽取的血样来评估FDPK的药代动力学。 For each treatment, a blood sample drawn from a subject according to assess the pharmacokinetics FDPK. 在FDKP吸入粉末的吸入之前和之后进行了肺参数(FEVl)的测量。 For and after lung parameters (FEVl) prior to measurement of the inhalation powder is FDKP. 这些实验的结果如表7和图36和37所示。 The results of these experiments are shown in Table 7 and FIGS. 36 and 37 shown in FIG.

[0253] 实验结果的代表性数据如下表7所示,表7图示了对于被测试的受试者、所测量的FDKP的平均AUCV6hr以及平均Cmax。 Representative Data [0253] The results shown in Table 7 below, Table 7 illustrates a subject to be tested, the average measured AUCV6hr FDKP and an average Cmax.

[0254]表 7 [0254] TABLE 7

[0255] [0255]

Figure CN102985125AD00421

[0256] 图36描述了由传感装置所监测到的、以IOmg剂量的FDKP利用DPIl的受试者的概括的示例,其示出了约4秒的无粉末练习吸入和约I秒的有FDKP粉末剂量的给药吸入。 [0256] FIG. 36 depicts an example summarized by the sensing means is monitored, using FDKP at dose IOmg DPIl subject, which shows about 4 seconds inhalation powder-free exercises has about I second FDKP powder dose inhalation administration. 图36还示出了药盒的排放量被重量地测量为10. 47mg,其导致FDKP全身接触的受试者的特征为AUCQ_6tos 等于31,433ng*min/mL。 FIG 36 also illustrates a kit emissions is measured as the weight 10. 47mg, which results in systemic exposure is subject FDKP wherein AUCQ_6tos equal 31,433ng * min / mL. 被输送的FDKP 粉末的标准化AUC/mg 是3. 003ng*min/mL每毫克。 FDKP powder conveyed normalized AUC / mg is 3. 003ng * min / mL per mg. 图37示出了6个小时所检测的在血浆中的FDKP浓度,该浓度示出了在约IOmin中约270ng/mL 的Cmax。 FIG 37 shows plasma FDKP concentrations detected six hours, the concentration is from about IOmin shows about 270ng / mL in Cmax.

[0257] 含有IOmg FDKP粉末的DPI I吸入系统输送到血液中的FDKP粉末是含有IOmgFDKP粉末的MEDTONE®吸入器的几乎两倍。 [0257] DPI IOmg FDKP powder containing I to FDKP powder inhalation system transporting blood containing almost twice IOmgFDKP MEDTONE® powder inhaler. 如显著的较高标准偏差所示,由于若干个体对于粉末不具有较好的接触性,平均含有15mg FDKP吸入粉末的DPI I吸入系统与含有IOmg粉末的DPI I系统的表现相比,没有输送成比例的剂量。 The standard deviation of significantly higher, since the powder does not have a number of individuals for better contact, containing an average performance 15mg FDKP inhalation powder inhalation system of DPI I containing powder DPI I IOmg system as compared to no delivery dose proportional. 在实验的部分I中的数据的变化可能是由于一些受试者在给药期间没有在正确的位置上使用吸入器。 Data changes in Part I above experiment may be due to some subjects do not use the inhaler in the correct position during the administration period.

[0258] 在表8中列出了对于更长时间、更短时间、更大的力或更小的力的吸入数据、DPII IOmg与MEDTONE®吸入系统的给药结果的比较。 [0258] For the data listed in the suction longer, shorter time, a larger or smaller force is the force in Table 8, and DPII IOmg comparison result MEDTONE® inhalation administration system. 如表8所示,分三部分进行研究。 As shown in Table 8, three parts studied. 表8图示了作为实验中获得的FDKP的平均AUCO-⑴的值测量的H)KP到肺循环的输送。 Table 8 illustrates the measured values ​​obtained in the experiments as FDKP mean AUCO-⑴ is H) KP delivery to the pulmonary circulation. 数据是与iML:L)_R)NL:.、R::吸入器系统相比的、DPI I吸入系统的有效性和性能的示例,并且示出了在将FDKP输送到全身血液循环方面、DPI I更有效,即优于MEDTONE®吸入器约30%,其中DPI I的值AUCchoJ人2375到5277ng*min/mL每毫克在制剂中排出的FDKP。 Data is iML: L) _R) NL:., Compared to the R :: inhaler system, DPI I effectiveness of the system and exemplary suction performance, and shows in FDKP delivered to the systemic circulation aspect, the DPI I is more effective, i.e., an inhaler MEDTONE® than about 30%, wherein the DPI 2375 I value AUCchoJ person to 5277ng * min / mL FDKP discharged per mg in the formulation. 在两次吸入后MEDTONE®的AUC0-j 1465到2403ng*min/mL每毫克在制剂中排出的FDKP。 After two suction MEDTONE® the AUC0-j 1465 to 2403ng * min / mL FDKP discharged per mg in the formulation.

[0259] 表8在三部分研究中经由DPI I和MT输送的FDKP [0259] Table 8 via DPI I and MT FDKP delivered in three parts of the study

[0260] [0260]

Figure CN102985125AD00431

[0261] 根据FDKP血浆AUC所测量的、在输送FDKP方面DPI I设备输送IOmg FDKP比MEDTONE®更有效,其比MEDTONE®增加了几乎两倍。 [0261] The measured plasma AUC FDKP, DPI I IOmg FDKP ratio MEDTONE® conveying device in the conveying FDKP more effective, which increased by almost twice MEDTONE®. FDKP的输送与吸入时间和吸入作用力无关。 It has nothing to do with the delivery of FDKP inhalation time and inspiratory effort. 如通过FDKP AUC和改变关于FDKP AUC的吸入参数的影响所评估的,数据示出了DPI I相对于ML:L)_U.)Nl.::亦具有改善的生物利用度和效率。 And variations such as by the impact of FDKP AUC inhalation parameter FDKP AUC of the evaluated data is shown with respect DPI I ML: L) _U) Nl :: bioavailability and also has improved efficiency... 在该研究中的FDKP的Cmax大于DPI I ( 一次吸入)的约100ng/mL以及利用MEDTONE® (两次吸入)的较小值即96±30ng/mL。 Cmax FDKP in this study is greater than the DPI I (a suction) from about 100ng / mL and a smaller value using MEDTONE® (two inhalations), i.e., 96 ± 30ng / mL.

[0262]示例 9 [0262] Example 9

[0263] 示例性吸入系统的FDKP和胰岛素的生物利用度的改善 [0263] improve the bioavailability of insulin and FDKP inhalation system of the exemplary

[0264] 如根据胰岛素和FDKP的药代动力学(PK)所确定的,安排本研究来评估与MEDTONE_吸入器相比、由肺循环输送系统(DPI 2)输送的TECHNOSPHERE馨胰岛素吸入粉末(FDKP-胰岛素)的相对生物利用度。 [0264] As is insulin and FDKP pharmacokinetic (PK) of the determined arrangement of the present study to assess compared with MEDTONE_ inhaler delivered by the pulmonary delivery system (DPI 2) TECHNOSPHERE Xin insulin inhalation powder (FDKP - insulin) relative bioavailability.

[0265] 这是对健康志愿者的开放的、交叉的PK(胰岛素和FDKP)研究。 [0265] It is open to healthy volunteers, the cross PK (insulin and FDKP) study. 使用C-肽修正法来确定由吸入输送的胰岛素相对于内在源胰岛素的相对量。 Using C- peptide correction method to determine the relative amount of inherent endogenous insulin by inhalation delivery of insulin respect. 24个受试者(每臂12)被利用DPI 2给予6. 7mg和7. 3mg FDKP-胰岛素吸入粉末(分别是20U和22U胰岛素以及约10%胰岛素w/w),并且被利用MEDTONE®给予IOmg FDKP-胰岛素吸入粉末(30U胰岛素)。 24 subjects (12 per arm) is administered using a DPI 2 and 6. 7mg 7. 3mg FDKP- powder inhaled insulin (insulin 22U and 20U, respectively, and about 10% insulin w / w), and is administered using MEDTONE® IOmg FDKP- insulin inhalation powder (30U insulin). 随后,以研究的三路交叉臂利用DPI 2给予20U,或经由MEDTONE®给予30U。 Subsequently, three-way crossover study using DPI 2 administered arm 20U, or administered via MEDTONE® 30U. 在给药之前以及在给药后的7、15、30、60、120、240和360分钟时从受试者抽取血液样本,以评估每种疗法的药代动力学。 Prior to dosing and at 7,15,30,60,120,240 and 360 min after the administration of blood samples from the subject, to assess the pharmacokinetics of each therapy.

[0266] 数据显示,利用DPI 2的20U或22U胰岛素与由MEDTON丨D给予的30U胰岛素相比,表现出相似的暴露量(exposures)。 [0266] data, using a DPI 2 20U or 22U 30U insulin compared with insulin administered by MEDTON Shu D, exhibit similar exposure (exposures). 对于胰岛素,血浆暴露量(AUCch21JDPI 2 20U 和MI..:UTONI.:® 30U 分别是3407± 1460uUxmin/m 和4,15±1,682uU*min/mL,并且含有22U 的DPI 2 和MI:DTC)NI: K 30U 分别是4,661 ±2,218uU*min/mL 和3,957±l,519uU*min/mL。 Insulin, plasma exposure (AUCch21JDPI 2 20U and MI ..: UTONI.:® 30U were 3407 ± 1460uUxmin / m and 4,15 ± 1,682uU * min / mL, and contains the MI 22U and DPI 2: DTC ) NI: K 30U were 4,661 ± 2,218uU * min / mL and 3,957 ± l, 519uU * min / mL. 在三路交叉臂中,DPI 2和MEDTONE®的血浆胰岛素暴露量分别是4,091 ± 1,189uU*min/mL 和3,763 ± 1,652uU*min/mL。 In the three-way cross arm, DPI 2 and MEDTONE® plasma insulin exposures were 4,091 ± 1,189uU * min / mL and 3,763 ± 1,652uU * min / mL.

[0267] 三路研究的结果还显示出胰岛素的Tmax从MLDTONL:.R的20. 8± 18. 7分钟减小到DPI 2 (20U)的14. 8±8. 94分钟,并且减小到DPI 2 (22U)系统的13. 6±4. 3分钟。 [0267] The results of the three-way studies also show insulin Tmax from MLDTONL:. .R of 20. 8 ± 18. 7 minutes to reduce the DPI 2 (20U) of 14. 8 ± 8 94 minutes, and reduced to 13. 6 ± 4. 3 minutes DPI 2 (22U) system. 在三路交叉研究中,其中在DPI 2中输送了6. 7mg的FDKP-胰岛素,在M丨iDTONL必中输送·了IOmg的FDKP-胰岛素,对所输送的量归一化的FDKP血浆暴露量(AUCch21J对DPI 2和MLD'1'ONl-CK 分别是2,059ng*min/mL/mg(16 个受试者剂量的平均值)和I, 324ng*min/mL/mg(17个受试者剂量的平均值)在该示例性实施例中,在粉末制剂中约10%的胰岛素含量的条件下进行生物利用度研究。因此,较高的生物利用度(为针对粉末含量进行归一化)可通过提供较高浓度的胰岛素来获得,并且相似的结果可以利用其它的活性成分来实现。类似的,含有较高含量的活性成分的制剂将会产生FDKP的较低的生物利用度(未针对粉末含量进行归一化)。 In the three-way crossover study in which are conveyed in a DPI 2 FDKP- 6. 7mg of insulin, will be conveyed in a IOmg · M of insulin FDKP- Shu iDTONL, the amount of delivered normalized plasma FDKP exposure ( AUCch21J of DPI 2 and MLD'1'ONl-CK are 2,059ng * min / mL / mg (16 subjects the average dose) and I, 324ng * min / mL / mg (17 subjects average dose) in this exemplary embodiment, a bioavailability study in the powder formulation at about 10% of the insulin content. Thus, higher bioavailability (as performed for the powder content normalized) It may be achieved by providing a higher concentration of insulin, and similar results can be achieved with other active ingredients. Similarly, the formulation containing the active ingredient will produce high levels of low bioavailability of FDKP (not for powder content is normalized).

[0268] 总的来说,如根据胰岛素血浆暴露量所测量的,DPI 2在输送胰岛素时比MEDTONE®更有效。 [0268] In general, the plasma insulin as measured in accordance with the amount of exposure, DPI 2 MEDTONE® more effective than insulin in the transportation. DPl 2系统以20U的胰岛素表现出与MEDTONE®利用30U的胰 DPl 2 system exhibits pancreatic insulin 20U and 30U of use MEDTONE®

岛素、相似的胰岛素暴露量。 Insulin, a similar insulin exposure.

[0269] 在下面的表格中呈现了上述实验的进一步结果。 [0269] Further results of the above experiment are presented in the following table. 在另外两个部分中进行了在上一示例中描述的研究。 Were studied in the previous example described in the other two parts. 在该研究的第二部分,受试者被利用DPI2给予了IOU在FDKP干粉制剂中的胰岛素,或被利用MEDTONE®吸入系统给予了15U在FDKP中的胰岛素。 In the second part of the study, subjects were given using DPI2 IOU insulin FDKP dry powder formulation, or administered using the inhalation system MEDTONE® 15U of FDKP insulin. 在该研究的第三部分,在三路交叉研究中,受试者被利用DPI 2给予了20U在FDKP制剂中的胰岛素,或被利用MEDTONE®吸入系统给予了30U在FDKP中的胰岛素。 In a third part of the study, the three-way crossover study, subjects were given using DPI 2 20U insulin FDKP formulation, or administered using the inhalation system MEDTONE® 30U of FDKP insulin. 测量了血液中的胰岛素浓度并且分析并评价了结果。 Measuring the insulin concentration in blood and the results are analyzed and evaluated.

[0270] 从被利用DPI 2 20U胰岛素治疗的受试者得到的血浆胰岛素和FDKP暴露量(AUC0-2hr)与从利用MEDTONE®吸入器的受试者得到的相似。 [0270] FDKP and plasma insulin from the subject using DPI 2 20U insulin therapy resulting exposure (AUC0-2hr) obtained from a similar subject using MEDTONE® inhaler. 数据在表9中示出。 Data shown in Table 9. 所示出的值是从使用20U胰岛素的DPI 2的所有服药的组、部分I和部分III中得到的,而关于MEDTONE®吸入器30U胰岛素的值是从部分1、11和III中得到的。 Value shown is the use of insulin 20U DPI all medication group 2, Part I and Part III obtained, and the values ​​for MEDTONE® 30U insulin inhaler is obtained from the portion 11, and III. 对于DPI 2 22U、低于预期的AUC胰岛素血浆暴露量胰岛素比在胰岛素的终端消除阶段时间点不足够更有可能次要。 For DPI 2 22U, lower than the expected AUC of plasma insulin insulin exposure time than the terminal elimination phase is not enough insulin is more likely secondary. 认识到后面的时间点的一些对AUC的计算没有帮助,并且修正转移到改善AUClast结果的时间序列。 Recognizing that some do not contribute to the calculation of AUC later time point, and proceeds to the correction time series AUClast improved results. 在完成了DPI 2 22U组之后的胰岛素药代动力学的变化改善了后来的浓度时间曲线。 After the completion of the change of DPI 2 22U insulin pharmacokinetics group improves subsequent concentration-time curve. 较低剂量的DPI 2 IOU和MEDTONIr:®吸入器15U也是类似的。 Lower dose DPI 2 IOU and MEDTONIr: ® inhaler 15U is similar. 在图38中描绘了来自所有个体的胰岛素浓度。 It depicts insulin concentrations in all individuals from FIG. 38. 来自DPI 2 20U和MEDTONE®吸入器30U以及来自DPI 210U和MEDTONE®吸入器15U的FDKP暴露量都落在了生物等效性标准内。 30U and FDKP from MEDTONE® inhaler DPI 210U and 15U exposure amount from the DPI 2 20U and MEDTONE® inhaler fall within the bioequivalence criteria. FDKP暴露量和胰岛素暴露量有良好的相关性。 FDKP insulin exposure and exposure have good correlation. 在图39中以剂量组描述了来自所有个体的FDKP浓度。 In FIG 39 described FDKP concentration dose groups from all individuals.

[0271] 表9中的数据是这里所公开的吸入器系统性能的表示,并且示出了所测量的实验中的受试者的平均血浆值AUCVinf为,每毫克利用两次吸入的MEDTONE®棑出的FDKP是1,879到3,383ng*min/mL,每毫克利用DPI 2单次吸入后的制剂中的被排出FDKP是2,773到5124ng*min/mL。 Data in Table 9 [0271] is disclosed herein a system inhaler performance, and shows the average plasma values ​​measured AUCVinf experiments subject, per milligram using two inhalation MEDTONE® raft FDKP out is 1,879 to 3,383ng * min / mL, is discharged FDKP inhalation formulation 2 after a single use per milligram to 2,773 DPI is 5124ng * min / mL. 数据还示出了,所有受试者的制剂中的被排出FDKP重量的每毫克的平均AUC 大于3,500 或3,568ng*min/mL。 The data also shows, the mean AUC per mg of FDKP discharged by weight greater than 3,500 or 3,568ng * min / mL of the formulation in all subjects.

[0272] 在研究中对于DPI 2的血浆胰岛素平均AUCV2to范围是在单次吸入中给予的粉末制剂中的每单位的胰岛素约96至315ng*min/mL,其中胰岛素的平均值是在单次吸入中给予的粉末制剂中的每单位胰岛素168至216ng*min/mL。 [0272] A powder formulation for DPI range of 2 AUCV2to average plasma insulin is administered in a single inhalation study in insulin per unit of from about 96 to 315ng * min / mL, with a mean insulin in a single inhalation per unit of insulin administered in the powder formulation of 168 to 216ng * min / mL. M卜:丨)TON的AUC0_inf (AUC0_)值是在两次吸入后给予的粉末制剂中的每单位胰岛素从约76至约239ng*min/mL。 M Bu: Shu) of the TON AUC0_inf (AUC0_) value per unit of insulin powder formulation after two inhalation administration is from about 76 to about 239ng * min / mL. 先前已经注意到,Ml:l)_rONI.吸入器系统的第一次吸入供给小于每个通常使用的药盒(数据未示出)两次吸入所排出的总胰岛素的一半,并且当FDKP用作在直接中的输送代表物时呈·现出相同的特性。 Has been previously noted, Ml: l) _rONI inhaler first suction system is less than half of the total supply of insulin discharged per kit (data not shown) commonly used in the inhalation twice, and when the FDKP used. It was exhibited the same characteristics · conveying in direct representatives.

[0273] 在利用DPI 2或\仆:.1.)_1()灿::《)给予了胰岛素之后,对各个受试者在用于建立胰岛素C-肽关系的测试餐期间以及在餐挑战期间评估了餐后血糖偏移。 [0273] using DPI 2 or \ servant: After .1) _ 1 () :: Can ") has given insulin, the various subjects during the test meal is used to establish the relationship between insulin C- peptide and the meal challenge evaluation of the postprandial blood glucose during the shift. 在图40中显示了DPI 2或MEDTONE®相比较的在各个个体中的血糖偏移。 DPI 2 shows blood glucose or MEDTONE® phase shift in the respective individual comparator 40 in FIG. 在研究中使用的剂量没有针对个体进行滴定,因此反应的大小随着个体不同而不同,但是在各个个体中可看出在利用两种吸入器的疗法之间通常可比较的血糖偏移。 Doses used in the study for the individual titration not performed, the size of the reaction vary from individual to individual, but in each individual can be seen between the inhaler using two treatments generally comparable glucose offset.

[0274] 还根据与利用放射性标记的FDKP通过静脉注射给予的延胡索酰二酮哌嗪或FDKP并测量为AUC、AUC0_的生物利用度相比较、来评估了吸入器的生物利用度。 [0274] Also according to FDKP by using radioactively labeled fumaric acid diketopiperazine or FDKP administered intravenously and is measured as the AUC, bioavailability AUC0_ compared to assess the bioavailability of the inhaler. 该研究的结果显示:N丨I」.I)_I ONE®系统的生物利用度被计算为对于IOmg和20mg被输送的FDKP粉末分别约为26%和32%。 The results of this study show that: N Shu I ".I) _I bioavailability ONE® system is calculated to be delivered to the IOmg and 20mg of FDKP powder about 26% and 32%, respectively. 与由静脉注射给予的IOmg FDKP相比,在模型分析中测量得到的利用DPI I输送IOmg FDKP的生物利用度是57%。 Compared with IOmg FDKP administered by the intravenous injection, measured in the model analysis using DPI I conveyance IOmg FDKP bioavailability is 57%. 如通过利用DPI 2和粉末的单次吸入的FDKP的AUCchooK测量的,利用FDKP-胰岛素制剂获得的数据的模型分析被用来评估吸入器性能分析或被输送粉末的有效性。 Such as by inhalation using a DPI and a single AUCchooK FDKP powder measuring 2 analysis was used to evaluate the effectiveness of inhaler performance analysis or transports the powder formulation of insulin using a model FDKP- data obtained. DPI 2将6. 7mg总量中的64%的FDKP输送到血液循环中,而MEDTONE®利用两次吸入输送46%o对于该FDKP-胰岛素制剂,FDKP含量大约是6mg。 DPI 2 6. 7mg total amount of 64% FDKP delivered to the bloodstream, while using two inhalation delivery MEDTONE® 46% o for the FDKP- insulin formulations, the content of FDKP about 6mg.

[0275] 图9利用FDKP-胰岛素粉末制剂的!7DKP和胰岛素药代动力学参数 [0275] FIG. 9 using the powder formulation of insulin FDKP-! 7DKP insulin and pharmacokinetic parameters

[0276] [0276]

Figure CN102985125AD00461

[0277]示例 10 [0277] Example 10

[0278] 基于C-肽修正的胰岛素浓度值和几何平均值的药代动力学参数 [0278] Kinetic parameters based on the correction insulin C- peptide concentration value and the geometric mean of the pharmacokinetic

[0279] 在如示例9所述进行的研究臂中,利用阶段I、开放的、随机的交叉的研究草案对46个健康志愿者进行了研究。 [0279] The arms of the study carried out in Example 9, using Phase I, open, randomized crossover study a draft of 46 healthy volunteers were studied. 进行研究以评价与每个药盒需要两次吸入来输送剂量的ML:L)TONU相比、利用需要单次吸入以输送装在药盒中的剂量的DPI 2给予的FDKP-胰岛素制剂的生物等效性。 Studies were conducted to evaluate the ML two inhalations each cartridge needs to deliver dose: L) TONU compared to using a single inhalation need to transport biological FDKP- insulin preparations contained in the kit of the administered dose DPI 2 equivalence. 此外,进行实验以评价利用DPI 2吸入器和通过口腔吸入服用FDKP-胰岛素制剂、输送给受试者胰岛素浓度的、装有IOU剂量的两个药盒的FDKP-胰岛素吸入粉末剂量是否生物等效于含有20U剂量的一个药盒。 In addition, experiments were performed to evaluate the use of the inhaler DPI 2 and oral inhalation administration by FDKP- insulin preparation, the insulin concentration delivered to a subject, the kit containing two doses IOU FDKP- whether inhaled insulin powder dose bioequivalent kit containing a dose of 20U. 受试者利用DPI 2或MEDTONtD通过口腔吸入被给予FDKP-胰岛素。 Subjects using DPI 2 by oral inhalation or MEDTONtD FDKP- insulin is administered. 受试者利用DPI 2吸入器接受单剂20U胰岛素、两剂IOU胰岛素或者利用MEDTONE®吸入器接受30U胰岛素。 Using DPI 2 subjects received a single dose inhaler 20U insulin, or with insulin IOU two MEDTONE® receiving 30U insulin inhaler. 在2个小时内的不同时间处从被治疗的各个个体采集血液样本。 At different times within two hours of blood samples collected from each individual being treated. 分析样本来测量胰岛素浓度。 Analysis of samples was measured insulin concentration. 研究的药代动力学参数是基于C-肽修正的浓度值的。 Pharmacokinetic Parameters of C- peptide is based on the concentration value of the correction. 从研究获得的结果在下面的表10中示出。 The results obtained from studies in Table 10 shown below.

[0280] 数据显示,使用利用DPI 2输送系统利用FDKP-胰岛素制剂通过口腔吸入给予个体的20U胰岛素,统计上生物等效于利用MEDTONE⑩吸入器给予30U相同的制剂。 [0280] Data shows that the use of the delivery system using DPI 2 FDKP- insulin formulations by oral inhalation administration 20U insulin individual, statistically bioequivalent to use an inhaler MEDTONE⑩ 30U are given the same formulation. 数据还显示,用DPI 2吸入器通过口腔吸入给予两个IOU剂量的FDKP-胰岛素制剂,与用相同的吸入器类型或DPI 2给予单剂20UFDKP-胰岛素制剂的胰岛素相比,产生相似的胰岛素全身暴露量。 The data also show that with the DPI inhaler 2 FDKP- insulin preparation administered two doses IOU through the mouth, the administration of insulin 20UFDKP- 2 insulin preparation in comparison with a single dose of the same type or the DPI inhaler, produce similar systemic insulin exposure. 因此,利用DPI 2吸入器系统和通过肺吸入给予,两剂IOU胰岛素的FDKP-胰岛素制剂与单剂20U胰岛素在血液循环中产生生物等效的胰岛素浓度。 Thus, with the inhaler DPI 2 and by pulmonary inhalation system, two IOU FDKP- insulin insulin insulin formulation produced a single dose bioequivalent 20U insulin concentrations in the blood circulation. 生物利用度数据还显示,利用DPI 2使患者服药,至少如胰岛素/FDKP制剂所例示的,利用该吸入系统给药,剂量给药表现为线性并且至少对于所测试的胰岛素范围或者从IOU到30U范围是成比例的。 The data also show bioavailability, patient medication using DPI 2, at least such as insulin / FDKP formulations illustrated embodiment, the systemic administration using inhalation, showed linear dose of insulin and at least for the range tested or to 30U IOU It is proportional to the range. ·[0281] 结果还显示,在输送相同剂量的制剂时,DPI 2输送系统以约33%的程度更有效。 * [0281] The results also show that when the same dose of the formulation delivery, DPI 2 delivery system to the extent of about 33% more efficient. 因此,与MEDTONE®!吸入器相比,DPI 2在剂量减少33%的条件下提供相同的胰岛素剂量暴露量。 Thus, as compared with MEDTONE®! Inhaler, DPI 2 provides the same reduction in the dose of insulin dose exposure under conditions of 33%.

[0282]表 10 [0282] TABLE 10

[0283] [0283]

Figure CN102985125AD00471

[0284] 示例11 [0284] Example 11

[0285] 基于指标利用体外吸入性能的吸入概况的特征 [0285] wherein based on the index before using in vitro performance of the inhalation

[0286] 这里所述的吸入系统由干粉吸入器(DPI 2)和药盒构成。 [0286] inhalation system described herein by dry powder inhaler (DPI 2) and configured kits. DPI 2与如美国专利申请No. 12/488,469 (US 2009/0314292,其教导的所有与吸入器操作和作用力及其测量有关的内容,通过引用结合于此)中公开的BLUHALE™设备一起使用,该设备测量在吸入动作期间和之后的时间段内在吸入器中产生的压力差。 DPI 2 and as described in U.S. Patent Application No. 12 / 488,469 (US 2009/0314292, all the suction force of the operation and its measurement content related to its teachings incorporated herein by reference) BLUHALE ™ apparatus disclosed used together, the device measures the pressure generated in the inhaler and after the period of action during inhalation difference. 图41是DPI 2的曲线示例,其中测量了在单次吸入期间和之后的共5秒的周期的跨吸入器的压力差。 FIG 41 is a graph of exemplary 2 DPI, which is measured during a single inhalation of the total cross inhaler period of 5 seconds and after a pressure differential. 在第二秒的峰值吸入压力,即PIP(2)表示在吸入开始以后的第一个两秒期间获得的曲线上的最高点或者最大压力。 In the second peak of the second suction pressure, i.e., PIP (2) represents the highest point on the curve during the first two seconds after the start of the suction is obtained or the maximum pressure. 图41示出了DPI 2的PIP(2)大约是5kPa并且在I秒内的曲线下面积或AUC(I)是3.7kPa*sec。 FIG 41 shows DPI PIP 2 (2) about 5kPa and the AUC or area under the curve (I) is in the second I 3.7kPa * sec.

[0287]示例 12 [0287] Example 12

[0288] 基于粒度直径测试的吸入器性能阈值测试 [0288] Based on the performance of a particle size diameter of the test inhaler threshold test

[0289] 在这些实验中使用了DPI 2类型的吸入器。 [0289] DPI 2 used a type of inhaler in these experiments. 各个吸入器装载有含有干粉制剂(包含包括胰岛素和FDKP的微粒)的药盒以测试设备的性能。 Each inhaler containing a dry powder formulation loaded with a cartridge (including particles comprising insulin and FDKP) is to test the performance of the device. 如上面的示例11中所例示的,吸入器先前已经被用于收集吸入概况。 11 as in the example above illustrated, the inhaler has been used previously collected before inhalation. 在利用BLUHALE™收集了吸入概况之后,吸入器被用于如专利申请No. PCT/US2010/055323 (其教导的所有与吸入器操作和作用力及其测量有关的内容,通过引用结合于此)所述的吸入模拟器,以由用户来再现示例性吸入。 After collecting suction before use BLUHALE ™, the inhaler is used (all the suction force of the operation and its measurement content related to its teachings incorporated herein by reference) as described in Patent Application No. PCT / US2010 / 055323 said suction simulator to be reproduced by the user exemplary inhalation. 使用模拟器的吸入概况然后被应用于从两个吸入器将粉末排放到如上面的示例2所述的激光衍射设备、以测量粒径分布。 Before using the suction is then applied to the simulator from two powder inhalers as in the example above is discharged to the apparatus of claim 2 laser diffraction to measure particle size distribution. 激光衍射设备测量体积中值几何直径(VMGD)。 A laser diffraction apparatus for measuring a volume median geometric diameter (VMGD). 如果被排出的颗粒的50%的直径小于4. 88 um,则认为值是可接受的,4. 88 um是基于对于DPI 2使用最佳的粒径的平均值增加33%而选择的。 If 50% of the particles discharged diameter of less than 4. 88 um, the value is considered to be acceptable, 4. 88 um is based on an average value using optimum particle size DPI 2 33% selected. 具有粉末药物的两个吸入器被装载到激光衍射设备中,并且以不同的吸入概况即不同的PIP(2)和AUC(I)值得到粉末排放或排出。 Two powdered medicament inhaler with laser diffraction is loaded into the apparatus and with different profiles, ie different suction PIP (2), and AUC (I) worthy to powder discharge or discharge. 测试对每个吸入器重复5次、共进行了10次测量,并且分析并绘制了数据。 The test was repeated 5 times for each inhaler, were carried out 10 measurements, and the data analyzed and plotted. 图42示出了以两个吸入器的PIP(2)与AUC(I)的图表示出了实验的结果,其中在图表中的每个点代表10次排放的平均值。 Figure 42 shows the inhaler in FIG PIP two (2) and AUC (I) show results of experiments in which each point in the graph represent average of 10 emissions. 在所有排放期间,药盒排空率(或被排出的干粉)都大于87%。 During all emissions, cartridge emptying (powder discharged or) greater than 87%. 图表的三角形吸入边界区表示图表中对于给定AUC(I)值的设备物理上不可能获得PIP(2)值的区域。 Triangular graph showing the suction boundary region for a given area of ​​the chart AUC (I) could not be obtained physical value PIP device (2) value. 被认为已经通过基于上述说明的标准并且在图42中的Gen 2通过标准线的上方和右方的吸入动作具有可接受的性能。 Is considered acceptable performance criteria based on the above description and to the right and above the Gen 2 standard line in FIG. 42 by the suction action has been. 图42中的数据显示,本设备的可接受性能的下限是大约2kPa的PIP (2)和至少I. 2kPa*sec的AUC (I)。 The data in Figure 42 show, the lower limit of acceptable performance of the present apparatus is approximately 2kPa the PIP (2) at least I. 2kPa * sec and the AUC (I). 然而,在其他实施例中,也已证明了至少约I. OkPa^sec或至少I. lkPa*sec的AUC(I)的可接受性能。 However, in other embodiments, it has also demonstrated at least about, or at least I. OkPa ^ sec I. lkPa * sec of AUC (I) of acceptable performance.

[0290] 前面的公开是示例性实施例。 [0290] The foregoing embodiments are exemplary disclosed embodiment. 本领域的技术人员应该明白,这里所公开的设备、技术和方法说明了在本公开的实践中功能良好的代表性实施例。 Those skilled in the art will appreciate, devices, techniques and methods disclosed herein illustrate the practice of the present disclosed function well in a representative embodiment. 然而,在本公开的启示下,本领域的技术人员将理解,在不脱离本发明的精神和范围的条件下,在所公开的具体实施例中可以作出很多改变,并且这些改变仍然可以得到相似或相同的结果。 However, in light of the present disclosure, those skilled in the art will appreciate that without departing from the spirit and scope of the present invention, in the particular embodiment disclosed may make many changes, and these changes can still get similar or the same result.

[0291] 除非另有说明,在说明书和权利要求书中使用的表示成分、诸如分子量、反应条件等的性质的所有数字,被认为通过术语“大约”在所有情况下可修改。 [0291] Unless otherwise indicated, all numbers properties used in the specification and claims expressing quantities of ingredients, such as molecular weight, reaction conditions, etc., are considered "about" may be modified in all instances by the term. 因此,除非相反地说明,在下面的说明书和权利要求书中所述的数字参数都是可以根据由本发明获得的所需性质而变化的近似值。 Accordingly, unless indicated to the contrary, in the following description and set forth in the claims is the numerical parameters may vary depending upon the desired properties of the present invention is obtained by the approximation. 最低限度地并且不试图限制权利要求的范围的等同物的教导的应用地,每个数字参数至少被解释为关于所报告的明显数字和通过四舍五入得到的数字。 Application of the teachings minimally and are not intended to limit the scope of the claims of the equivalents thereof, each numerical parameter should at least be construed as being obvious on the reported figures, and the number obtained by rounding. 尽管描述本发明的较宽范围的数字范围和参数是近似值,但是在具体示例中所陈述的数值是尽可能精确地报告的。 While the description of the present invention a wide range of numerical ranges and parameters are approximations, but in a specific example of numerical values ​​set forth are reported as precisely as possible. 然而,任何数值固有地包含由在它们的各自的测试测量中发现的标准偏差所必然导致的某些误差。 However, any numerical value inherently contains certain errors from the standard deviation found in their respective testing measurements necessarily resulting. ' '

[0292] 在描述本发明的上下文中(尤其是在后面的权利要求书的上下文中)所使用的术语“一”、“一个”和“这个”以及类似的表示,除非被指出或与上下文明确地相抵触,均解释为覆盖单数和复数。 [0292] In the context of describing the invention (especially in the back of the claims context) used the term "a", "an" and "the" and similar representation, unless stated or the context clearly the conflict, are construed to cover both the singular and the plural. 这里的值的范围的陈述仅仅意图用作单独地指落在范围内的每个独立的值的速记方法。 Recitation of ranges of values ​​herein are merely intended to serve as a shorthand method of referring individually to each separate value falling within the range. 除非这里被指出,每个单独的值就像其在这里被单独地陈述一样结合到说明书中。 Unless it indicated herein, and each separate value as if it were individually set forth herein as incorporated into the specification. 除非这里被指出或者与上下文明确地相抵触,这里所述的所有方法可以任何适合的顺序执行。 Unless indicated herein or clearly contradicted by context, all the methods described herein may be performed in any suitable order. 这里所提供的任何和所有示例或示例性语言(例如,“诸如”)仅意图更好地说明本发明,并且除另有声明外不对本发明的范围进行限制。 Any and all examples, or exemplary language provided herein (e.g., "such as"), is intended merely to better illustrate the present invention Unless stated otherwise, and not to limit the scope of the invention. 说明书中的语言不解释为指示本发明的实践所必须的任何未要求保护的组件。 Specification language not to be construed as indicating any components necessary for practice of the invention the non-claimed.

[0293] 在权利要求书中的术语“或”的使用,虽然本公开支持仅引用替代物以及“和/或”的限定,除非明确地指示仅引用替代物或替代物相互排斥,否则即用来意指“和/或”。 [0293] In the claims, the term "or" is used, although the disclosure supports only alternative reference well defined "and / or" unless explicitly indicated to refer only to substitute or alternatives are mutually exclusive, i.e., with or to mean "and / or."

[0294] 这里所公开的本发明的替代组件或实施例的分组不解释为限制性的。 [0294] Alternative embodiments of the present invention, or components herein disclosed embodiments of the packet is not to be construed as limiting. 每个组的部件可以单独地或以与组的其他部件任何组合或这里所发现的其他组件指代并且要求。 Each group member may be used alone or with other components in any combination or set of other components found herein and refer to requirements. 期望为了方便和/或可专利性,组的一个或多个组件可以包含在组内或从组内删除。 Desirable for convenience and / or patentability, groups of one or more components may be contained within a group or deleted from the group. 当这样的包括或删除发生时,说明书在这里被认为包含被修改的组,从而实现在权利要求中使用的所有马库什组的已写说明书。 When such inclusion or deletion occurs, the specification is herein deemed to contain the group as modified thus achieved in the written description of the claims of all Markush groups. · ·

[0295] 这里描述了本发明的优选实施例,包括发明人所知的实施本发明的最好方式。 [0295] herein described preferred embodiments of the present invention, including the best mode embodiment of the invention known to the inventors. 当然,阅读了上面的说明以后,这些优选实施例的变体对本领域的普通技术人员将显而易见。 Of course, after reading the above description, such variations of the preferred embodiment of ordinary skill in the art will be apparent. 发明人希望本领域的技术人员适当地使用这些变体,并且发明人意图以除了这里所具体描述地方式实施本发明。 The inventors expect skilled in the art to use such variations as appropriate, and the inventors intend for the embodiment of the present invention except that herein be specifically described. 因此,本发明包括在如适合的法律所允许的所附权利要求中所述的主题的所有修改和等同物。 Accordingly, the present invention includes the subject matter described as permitted by law for the appended claims all modifications and equivalents thereof. 而且,以各种可能的变化的上述元件的任何组合被包含在本发明中,除非这里被指出或与上下文明确地相抵触。 Further, any combination of a variety of possible variations of the elements is included in the present invention, unless indicated herein or clearly contradicted by context.

[0296] 这里所公开的具体实施例可以利用包括或主要包括语言在权利要求书中进一步被限制。 [0296] Specific embodiments disclosed herein may be utilized include or comprise the features language further limited in the claims. 当在权利要求书中使用时,无论是作为提交还是每次修改的补充,该过渡术语排除在权利要求中没有指出的任何元件、步骤或成分。 When used in the claims, whether as filed or added per modification, the transition term excludes any element, step, or ingredient not indicated in the claims. 过渡术语“主要包括”将权利要求的范围限制到具体的材料或步骤,以及没有本质地影响基本和新颖特性的材料和步骤。 The transition term "consisting essentially of" limits the scope of the claims to the specific materials or steps, and does not essentially affect the basic and novel characteristics of the materials and steps. 这里本质上地或清楚地描述并且使能了这样要求的本发明的实施例。 Here the nature or can be clearly described and the embodiment of the present invention thus claims.

[0297] 此外,在整个说明书中多次引用了专利和印刷出版物。 [0297] Further, throughout the description repeatedly cited patents and printed publications. 以上引用的文献和印刷出版物的各个在这里整体地通过引用单独地结合。 Each cited above documents and printed publications is herein integrally incorporated by reference individually.

[0298] 此外,应该明白,这里所公开的本发明的实施例是本发明的原理的说明。 [0298] Further, it should be understood that embodiments of the invention disclosed herein are illustrative of the principles of the present invention. 在本发明的范围内可以采用其他的修改。 Within the scope of the present invention, other modifications may be employed. 因此,以示例而非限制的方式,根据这里的教导可以利用本发明的替换配置。 Thus, by way of example and not limitation, the teachings herein may be utilized in accordance with an alternative configuration of the present invention. 因此,本发明不限于所示和所述的精确描述。 Accordingly, the present invention is not limited to the precise description shown and described.

Claims (23)

1. 一种干粉吸入器,包括: a)嘴部; b)容器壳体;以及e)至少一个刚性空气导管; 其中所述干粉吸入器被配置成,当通过所述嘴部的单次吸入在两秒内产生约2kPa的峰值吸入压力时,在单次吸入中从定位在所述容器壳体中的容器中作为粉末颗粒排出大于约75%的干粉,并且被排出的所述粉末颗粒具有小于约5微米的体积中值几何直径。 1. A dry powder inhaler, comprising: a) nozzle portion; b) a container housing; and e) at least one rigid air conduit; wherein the dry powder inhaler is configured to, when a single inhalation through the mouthpiece portion when the generation of the peak suction pressure of approximately 2kPa within two seconds, in a single inhalation from a container positioned in the housing in the container as the powder particles is greater than about 75% of the discharged powder, and the powder particles having been discharged less than about 5 microns volume median geometric diameter.
2.根据权利要求I所述的干粉吸入器,对空气流的阻力值的范围是从约0.065( V kPa)/liter 每分钟到约O. 200 ( V kPa)/liter 每分钟。 2. The dry powder inhaler according to claim I, the range of the resistance value of the air flow is from about 0.065 (V kPa) / liter per minute to about O. 200 (V kPa) / liter per minute.
3.根据权利要求I所述的干粉吸入器,其中所述干粉是用于肺部给药的制剂并且包括从约Img到约30mg的量的所述干粉。 3. The dry powder inhaler of claim I, wherein said formulation is a dry powder for pulmonary administration of the dry powder and comprising an amount of from about 30mg to about Img of.
4.根据权利要求I所述的干粉吸入器,其中所述干粉包括二酮哌嗪或药学上可接受的二酮哌嗪的盐。 4. A dry powder inhaler according to claim I, wherein the dry powder comprises acceptable salt or pharmaceutically diketopiperazine diketopiperazine.
5.根据权利要求4所述的干粉吸入器,其中所述二酮哌嗪的化学结构式是2,5- 二酮-3,6-二(NX-4-氨基丁基)哌嗪,其中X是从由延胡索酰、琥珀酰、马来酰和戊二酰构成的组中选取的。 5. The dry powder inhaler as claimed in claim 4, wherein the chemical structural formula of the diketopiperazine is 2,5-diketo-3,6-di (NX-4- aminobutyl) piperazine, wherein X It is selected from the group consisting of fumaric acid, succinic acid, maleic acid, and the glutaryl.
6.根据权利要求4所述的干粉吸入器,其中所述二酮哌嗪是(二次_3,6-(N-延胡索酰-4-氨基丁基)-2,5- 二酮-二酮哌嗪。 6. A dry powder inhaler according to claim 4, wherein said diketopiperazine is (secondary _3,6- (N- fumaric acid-4-amino-butyl) -2,5-dione - two ketopiperazine.
7.根据权利要求I所述的干粉吸入器,其中所述干粉包括药物或活性剂。 7. A dry powder inhaler according to claim I, wherein the dry powder comprises a medicament or an active agent.
8.根据权利要求7所述的干粉吸入器,其中活性剂是内分泌激素。 8. The dry powder inhaler of claim 7, wherein the active agent is a hormone.
9.根据权利要求I所述的干粉吸入器,其中所述干粉包括肽、多肽、或它们的片断、小有机分子或核酸分子。 9. A dry powder inhaler according to claim I, wherein the dry powder comprises a peptide, polypeptide, or fragments thereof, small organic molecules or nucleic acid molecule.
10.根据权利要求9所述的干粉吸入器,其中所述肽是胰岛素、胰高血糖素、胰高血糖素样肽I、甲状旁腺激素、催产素、胃泌酸调节素、肽YY、醋酸艾塞那肽、其类似物或其片段。 10. A dry powder inhaler according to claim 9, wherein the peptide is insulin, glucagon, glucagon-like peptide I, parathyroid hormone, oxytocin, stomach oxyntomodulin, peptide YY, exendin, analogs or fragments thereof.
11.根据权利要求9所述的干粉吸入器,其中所述小有机分子是血管扩张剂、血管收缩剂、神经递质受体激动剂或神经递质受体拮抗剂。 11. A dry powder inhaler according to claim 9, wherein said small organic molecule is a vasodilator, vasoconstrictor, neurotransmitter receptor agonists or antagonists of neurotransmitter receptors.
12.根据权利要求I所述的干粉吸入器,其中所述单次吸入产生至少约I. 0、1. I或1. 2kPa*sec的、来自压力与时间曲线的一秒内曲线下面积(AUC)。 12. A dry powder inhaler according to claim I, wherein said generating a single inhalation least about I. 0,1. I or 1. 2kPa * sec, the area under the curve within a second pressure versus time curve from ( AUC).
13.根据权利要求I所述的干粉吸入器,其中所述容器被集成到所述容器壳体中并且填充有干粉。 13. A dry powder inhaler according to claim I, wherein the container is integrated into the housing and the container is filled with powder.
14.根据权利要求I所述的干粉吸入器,其中所述吸入器不包括容器。 14. A dry powder inhaler according to claim I, wherein said container does not include inhaler.
15.根据权利要求I所述的干粉吸入器,其中所述容器与所述吸入器分开地设置并且填充有干粉。 15. A dry powder inhaler according to claim I, wherein said container is provided separately from the inhaler and filled with a dry powder.
16. 一种利用高阻力干粉吸入器输送粉末的方法,所述方法包括: 提供干粉吸入器,所述干粉吸入器具有从约0.065( V kPa)/liter每分钟到约O. 200 ( V kPa)/liter每分钟的范围的空气流阻力值,并且装有所述干粉的剂量; 施加足够的力以在2秒内达到至少2kPa的峰值吸入压力;以及产生至少约I. O、I. I或I. 2kPa*sec的、吸入压力与时间曲线的第一秒中的曲线下面积(AUCch1sJ ;其中所述干粉剂量的大于75%被作为粉末颗粒从所述吸入器排放或排出。 16. A method of using a high-resistance dry powder inhaler delivery of powder, the method comprising: providing a dry powder inhaler, a dry powder inhaler having from about 0.065 (V kPa) / liter per minute to about O. 200 (V kPa ) / liter per minute range of airflow resistance value, and with the dry powder dose; applying sufficient force to achieve a peak of at least 2kPa suction pressure within 2 seconds; and generating at least about I. O, I I. area under the curve in the first second or I. 2kPa * sec, the suction pressure versus time curve (AUCch1sJ; wherein greater than 75% is used as the dry powder dose inhaler powder particles from the exhaust or discharge.
17.根据权利要求16所述的方法,其中所述干粉是用于肺部给药的制剂并且包括从约Img到约30mg的量的所述干粉。 17. The method according to claim 16, wherein said formulation is a dry powder for pulmonary administration of the dry powder and comprising an amount of from about 30mg to about Img of.
18.根据权利要求17所述的方法,其中所述干粉包括二酮哌嗪或药学上可接受的二酮哌嗪的盐。 18. The method according to claim 17, wherein the dry powder comprises acceptable salt or pharmaceutically diketopiperazine diketopiperazine.
19.根据权利要求18所述的方法,其中所述二酮哌嗪的化学结构式是2,5- 二酮-3,6-二(NX-4-氨基丁基)哌嗪,其中X是从由延胡索酰、琥珀酰、马来酰和戊二酰构成的组中选取的。 19. The method of claim 18, wherein the chemical structural formula of the diketopiperazine is 2,5-diketo-3,6-di (NX-4- aminobutyl) piperazine, wherein X is selected from of fumaric acid, succinic acid, maleic acid and glutaryl group consisting of selected.
20.根据权利要求19所述的方法,其中所述二酮哌嗪是(二次-3,6-(N-延胡索酰-4-氨基丁基)-2,5- 二酮-二酮哌嗪。 20. The method according to claim 19, wherein the diketopiperazine is (secondary -3,6- (N- fumaric acid-4-amino-butyl) -2,5-dione - diketopiperazine triazine.
21.根据权利要求16所述的方法,其中所述干粉制剂包括从由小有机分子、肽、多肽、蛋白质或核酸分子构成的组中选取的药物或活性剂。 21. A method according to claim 16, wherein said formulation comprises a dry powder selected from the group consisting of small organic molecules, peptides, polypeptides, proteins or nucleic acid molecules of the drug or active agent.
22.根据权利要求21所述的方法,其中所述小有机分子是血管活性剂、神经递质受体激动剂、神经递质受体拮抗剂或类固醇分子。 22. The method of claim 21, wherein said small organic molecule is a vasoactive agent, neurotransmitter receptor agonists, receptor antagonists of neurotransmitters or steroid molecule.
23.根据权利要求20所述的方法,其中所述干粉制剂包括延胡索酰二酮哌嗪微粒,所述延胡索酰二酮哌嗪微粒从所述干粉吸入器排出以后被测量为具有从约2 μ m到8 μ m范围的体积中值几何直径(VMGD)以及小于4μπι的几何标准偏差。 23. The method according to claim 20, wherein the dry powder formulation comprises a diketopiperazine microparticles fumaric acid, a fumaric acid diketopiperazine microparticles is measured from the dry powder inhaler is discharged after having from about 2 μ [mu] m to m volume median geometric diameter range 8 (a VMGD) and geometric standard deviation of less than 4μπι.
CN2011800309664A 2010-06-21 2011-06-21 Dry powder drug delivery system and methods CN102985125A (en)

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US35703910P true 2010-06-21 2010-06-21
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US61/411,775 2010-11-09